Marketing Authorisations under Exceptional Circumstances ...eprints.hta.lbg.ac.at/992/1/HTA-Projektbericht_Nr.65.pdf · Marketing Authorisations under Exceptional Circumstances for

Marketing Authorisations under Exceptional Circumstances for Oncology Drugs

An analysis of approval and reimbursement decisions of four drugs

HTA-Projektbericht Nr.: 065 ISSN online 1992-0496


An analysis of approval and reimbursement decisions of four drugs

Vienna, January 2013

Projektteam (Project team) Projektleitung (Project leader): Annette van der Vossen, BSc Projektbearbeitung (Author): Annette van der Vossen, BSc Projektbeteiligung (Additional contribution) Interne Begutachtung (Internal review): Dr. med. Anna Nachtnebel MSc PD Dr. phil. Claudia Wild Korrespondenz (Correspondence): Annette van der Vossen, [email protected] Anna Nachtnebel, [email protected] Dieser Bericht soll folgendermassen zitiert werden/This report should be referenced as follows: Van der Vossen, AC., Nachtnebel, A. und Wild, C. Marketing Authorisations under Exceptional Circumstances for Oncology Drugs: An analysis of approval and reimbursement decisions of four drugs. (2013):HTA-Projektbericht 65. Wien: Ludwig Boltzmann Institut fu¨r Health Technology Assessment. Interessenskonflikt Alle beteiligten AutorInnen erkla¨ren, dass keine Interessenskonflikte im Sinne der Uniform Requirements of Manuscripts Statement of Medical Journal Editors (www.icmje.org) bestehen

Conflict of Interest All contributing authors declare that they have no conflicts of interest according to the Uniform Requirements of Manuscripts Statement of Medical Journal Editors (www.icmje.org)

IMPRESSUM

Medieninhaber und Herausgeber: Ludwig Boltzmann Gesellschaft GmbH Nussdorferstr. 64, 6 Stock, A-1090 Wien http://www.lbg.ac.at/de/lbg/impressum

Fu¨r den Inhalt verantwortlich:

Ludwig Boltzmann Institut fu¨r Health Technology Assessment (LBI-HTA) Garnisongasse 7/20, A-1090 Wien http://hta.lbg.ac.at/

Die HTA-Projektberichte erscheinen unregelma¨ssig und dienen der Vero¨ffentlichung der Forschungsergebnisse des Ludwig Boltzmann Instituts fu¨r Health Technology Assessment. Die HTA-Projektberichte erscheinen in geringer Auflage im Druck und werden u¨ber den Dokumentenserver „http://eprints.hta.lbg.ac.at“ der O¨ffentlichkeit zur Verfu¨gung gestellt: HTA-Projektbericht Nr.: 065 ISSN-online: 1992-0496 © 2013 LBI-HTA – Alle Rechte vorbehalten

mailto:[email protected]

mailto:[email protected]

http://www.icmje.org

http://www.icmje.org

http://www.lbg.ac.at/de/lbg/impressum

http://hta.lbg.ac.at

http://eprints.hta.lbg.ac.at%E2%80%9C

LBI-HTA | 2013 3

Contents

List of Abbreviations ........................................................................................................................................... 5

Summary................................................................................................................................................................ 7

1 Introduction .......................................................................................................................................................... 8 1.1 Aim and objectives ....................................................................................................................................... 9 1.2 Materials and Methods................................................................................................................................. 9

2 Background ......................................................................................................................................................... 11 2.1 EMA............................................................................................................................................................. 11

2.1.1 Authorisation procedures for medicinal products in the European Union ....................................11 2.1.2 Orphan Medicinal Product Designation .............................................................................................12 2.1.3 Applications in exceptional circumstances .........................................................................................13 2.1.4 Conditional approval .............................................................................................................................14

2.2 Reimbursement aspects ............................................................................................................................. 14 2.2.1 Healthcare systems introduction..........................................................................................................14 2.2.2 Reimbursement and financing aspects ................................................................................................15 2.2.3 Patient Access Schemes .........................................................................................................................20

3 Results.................................................................................................................................................................. 22 3.1 Oncology drugs under exceptional circumstances................................................................................... 22 3.2 Clofarabine – Evoltra ................................................................................................................................. 22

3.2.1 Indication ................................................................................................................................................22 3.2.2 Mechanism of action ..............................................................................................................................24 3.2.3 Summary of licensing documents ........................................................................................................25 3.2.4 Additional publications .........................................................................................................................26 3.2.5 Summary of reimbursement documents .............................................................................................27

3.3 Nelarabine – Atriance ................................................................................................................................ 28 3.3.1 Indication ................................................................................................................................................28 3.3.2 Mechanism of action ..............................................................................................................................29 3.3.3 Summary of licensing documents ........................................................................................................29 3.3.4 Additional publications .........................................................................................................................30 3.3.5 Summary of reimbursement documents .............................................................................................31

3.4 Trabectedin – Yondelis .............................................................................................................................. 32 3.4.1 Indication ................................................................................................................................................32 3.4.2 Mechanism of action ..............................................................................................................................33 3.4.3 Summary of licensing documents ........................................................................................................33 3.4.4 Additional publications .........................................................................................................................35 3.4.5 Summary of reimbursement documents .............................................................................................36

3.5 Ceplene – histamine dihydrochloride....................................................................................................... 38 3.5.1 Indication ................................................................................................................................................38 3.5.2 Mechanism of action ..............................................................................................................................38 3.5.3 Summary of licensing documents ........................................................................................................39 3.5.4 Additional publications .........................................................................................................................40 3.5.5 Summary of reimbursement documents .............................................................................................40

4 Discussion ........................................................................................................................................................... 42 4.1 EMA’s considerations and additional requirements................................................................................ 42 4.2 Reimbursement evaluations ...................................................................................................................... 44 4.3 Patient access and patient access schemes................................................................................................ 45 4.4 Conclusions and recommendations .......................................................................................................... 46

5 References............................................................................................................................................................ 47


4 LBI-HTA | 2006

List of Tables

Table 2.2-1: Main characteristics of the healthcare systems and reimbursement of pharmaceuticals of the countries included in the report....................................................................................................18

Table 2.2-2: Agencies and organisations involved in reimbursement decisions in the countries included in the report................................................................................................................................19

Table 3.2-1: Oncology drugs authorised under exceptional circumstances by the EMA.......................................23 Table 3.2-2: Publications on clinical trials and case reports of single-agent use of clofarabine

in patients with ALL .................................................................................................................................27 Table 3.2-3: Main remarks on different aspects from the reimbursement evaluations of clofarabine .................28 Table 3.3-1: Publications on clinical trials and case reports of single-agent use of

nelarabine in patients with ALL..............................................................................................................31 Table 3.3-2: Main remarks on different aspects from the reimbursement evaluations of nelarabine ..................32 Table 3.4-1: Main outcomes of study ET743-STS-201................................................................................................34 Table 3.4-2: Publications of single-agent use of trabectedin in patients with soft tissue sarcoma........................35 Table 3.4-3: Main remarks on different aspects from the reimbursement evaluations of trabectedin.................37 Table 3.5-1: Main remarks on different aspects from the reimbursement evaluations of

histamine dihydrochloride .......................................................................................................................41 Table 4.1-1: Compliance to additional requirements requested by the CHMP ......................................................43 Table 4.2-1: Reimbursement decisions per agency .....................................................................................................44

Contents

LBI-HTA | 2013 5

List of Abbreviations

ALL ....................... Acute Lymphoblastic Leukaemia

AML ...................... Acute Myeloid Leukaemia

ASMR.................... Amélioration du Service Médical Rendu

BMF ...................... Berlin-Frankfurt-Münster

BMT ...................... Bone marrow transplant

BSC ....................... Best Supportive Care

CED ...................... Coverage with Evidence Development

CFH ...................... Commissie Farmaceutische Hulp/Committee Pharmaceutical Aid

CHMP................... Committee for Medicinal Products for Human Use

CNS....................... Central Nervous System

CTC....................... Conditional Treatment Continuation

CVZ....................... College voor Zorgverzekeringen

DNA ...................... Deoxyribonucleicacid

EMA ...................... European Medicines Agency

EORTC STBSG.... European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group

EPAR .................... European Public Assessment Report

HAS....................... Haute Autorité de Santé

HDC...................... Histamine Dihydrochloride

HSCT .................... Hematopoietic Stem Cell Transplant

ICER ..................... Incremental Cost-Effectiveness Ratio

IL-2........................ Interleukin-2

LBL ....................... Lymphoblastic Lymphoma

LFS........................ Leukaemia Free Survival

NHS....................... National Health Service

NICE..................... National Institute for Health and Clinical Excellence

OS.......................... Overall Survival

PD ......................... Pharmacodynamics

PFS........................ Progression Free Survival

PK.......................... Pharmacokinetics

QALY .................... Quality adjustedlife-year

RIZIV.................... Rijks Instituut voor Ziekte – en Invaliditeits Verzekering

SCT ....................... Stem Cell Transplant

SMC ...................... Scottish Medicines Consortium

SMR ...................... Service Médical Rendu

STS ........................ Soft Tissue Sarcoma

TTP ....................... Time To Progression

VWS ...................... Health, Welfareand Sports

LBI-HTA | 2013 7

Summary

Background

Orphan drug regulation was created out of the idea that patients suffering from rare conditions should be entitled to the same quality of treatment as other patients.Some conditions however, are so rare that a thorough clinical development programme, normally required, is practically impossible. In these casesthe European Medicines Agency (EMA) can authorise a drug un-der exceptional circumstances.

Aim and research questions

This report aims to provide insight into the authorisation under exceptional circumstances of oncology drugs. We try to answer the following questions:

b What clinical data were presented by the applicant and what were the considerations by the Committee for Medicinal Products for Human Use (CHMP) for granting exceptional circumstances?

b What were the additional requirements to be fulfilled by the marketing authorisation holder?

b What additional data became available on the originally licenced indication and did it confirm the initial expectations?

b How do reimbursement agencies assess these drugs?

b Are there any patient access schemes for these drugs?

b Do the patients have access to the drugs?

Methods

This report considered oncology drugs currently licenced under exceptional circumstances. Reimbursement agencies from England, Scotland, Belgium, France and the Netherlands were included. A MEDLINE-search for litera-ture was performed through Pubmed and grey literature was included from EMA and the reimbursement agencies.

Results

Four oncologic drugs are currently licensed under exceptional circumstances; clofarabine, nelarabine, trabectedin and histamine dihydrochloride. Hista-mine dihydrochloride was the only drug tested in a phase III trial. For clo-farabine, nelarabine and trabectedin the justification for the authorisation under exceptional circumstances was the small size of the patient population. For histamine dihydrochloride it was unclear. Most of the additional re-quirements by the CHMP considered safety measures and they were not al-ways completed within the set time-frame.

The methods of the reimbursement assessments varied. One patient access scheme was identified for trabectedin in England. Some of the drugs were not accessible in some countries and for others it was unclear.

Conclusion and recommendation

To successfully develop drugs for very rare conditions, it is important that industry, EMA and reimbursement agencies intensify the collaboration. On introduction these drugs cannot always prove their cost-effectiveness, there-fore conditional coverage with evidence development, preferably on an in-ternational level, should be encouraged and facilitated.

background

aim and research questions

methods

results

conclusion and recommendations

8 LBI-HTA | 2013

1 Introduction

Since the founding of the European Medicines Agency (EMA) in 1995, over fifty novel oncologic drugs have reached the European market. Despite ad-vances in the development of cancer drugs in the last decades, there is still a high medical need for curative therapies. To accelerate patient access to new treatments in all fields of medicine and to stimulate research by pharmaceu-tical companies, the European Commission has laid down multiple regula-tions concerning marketing authorisation for pharmaceuticals.

As stated in Regulation (EC) No 141/2000, orphan drug regulation was cre-ated out of the idea that patients suffering from rare conditions should be entitled to the same quality of treatment as other patients. The pharmaceu-tical industry would be unwilling to develop the medicinal product for rare diseases under normal market conditions, because the costs of developing and bringing to the market of such a product would not be recovered by the expected sales [1].

Patients with such conditions deserve the same quality, safety and efficacy in medicinal products as other patients, therefore orphan medicinal prod-ucts are submitted to the normal evaluation process [1]. Some conditions however, are so rare that a thorough clinical development programme, nor-mally required, is practically impossible. In this case it is possible to get a marketing authorisation under exceptional circumstances [2].

There are some possible pitfalls to this policy. There are no extensive guide-lines on when exceptional circumstances are applicable, which gives the Committee for Medicinal Products for Human Use (CHMP) freedom to ap-ply them when they think it is appropriate. It also is unclear what the condi-tions and arguments are to apply this policy and whether they are justified.

Secondly, this policy somewhat contradicts the statement that patients with rare diseases deserve the same quality, safety and efficacy in medicinal prod-ucts as other patients. Especially the latter two aspects could be expected to be less convincing when a thorough clinical development programme is lacking.

Thirdly, it conflicts with the so called ‘fourth hurdle’ in drug development. To gain market access and reimbursement, the demonstration of clinical- and cost-effectiveness are in some countries a necessity [3, 4]. A limited clinical development programme could possibly not satisfy the requirements for reimbursement. For these reasons, it is thinkable that a marketing au-thorisation under exceptional circumstances might not always have its de-sired effect in providing safe and effective medicines to seriously ill patients.

Concerns have been raised by Niraula et al [5] about the safety of newly ap-proved cancer drugs in general. The greater efficacy of these drugs seems to come with an increase in morbidity and treatment-related mortality, owing to the toxicity of the treatments. This may be a consequence of the fact that oncology drugs are often approved without a phase III trial [6] and that the pivotal trial design for orphan oncology drugs, but also for non-orphan on-cology drugs, is often far from ideal [7-10].

A study conducted by EURORDIS in 2006 analysed the availability of 21 different orphan drugs in 28 European countries [11]. The results showed that there was a large variation in access to orphan drugs. Only in four coun-

rationale for orphan drug regulation

some conditions are too rare for a thorough

clinical development programme

no extensive guidelines on exceptional circumstances

lacking of thorough clinical development programme conflicts

with quality, safety and efficacy

more likely to not meet the requirements for

reimbursement

oncology drugs are often without

phase III trial

access to orphan drugs in Europe varies

Introduction

LBI-HTA | 2013 9

tries nearly all drugs were available to patients. The four oncologic drugs that were assessed in the EURORDIS study were available to around 70 % of the total population included.

In the past decade, a lot of attention has been given to orphan drugs and or-phan drug regulation. In this report, we focus explicitly on oncology drugs authorised under exceptional circumstances.

1.1 Aim and objectives

This report aims to provide insight into the authorisation under exceptional circumstances of oncology drugs by exploring the possible pitfalls presented earlier. We try to answer the following questions:

b What clinical data were presented by the applicant and what were the considerations by the CHMP for granting exceptional circumstances?

b What were the additional requirements to be fulfilled by the marketing authorisation holder?

b What additional data became available on the originally licenced indication and did it confirm the initial expectations?

b How do reimbursement agencies assess these drugs?

b Are there any patient access schemes for these drugs?

b Do the patients in the selected countries have access to the drugs?

1.2 Materials and Methods

Product selection

Drugs licensed under exceptional circumstances were identified via the web-site of the EMA using the European Public Assessment Report (EPAR) da-tabase. Only new chemical or biological entities, currently authorised under exceptional circumstances by the European Commission for anticancer treat-ment were included. Supportive therapies (e.g. bisphosphonates, immuno-globulins, antiemetics), colony-stimulating factors, chemoprevention treat-ments, vaccines and generics were excluded. Label extensions obtained after the initial marketing authorisation were not considered.

Selection reimbursement agencies

The main inclusion criteria for the reimbursement agencies were the exis-tence of publicly available assessment reports in Dutch, English or French and the nationwide reach of their advice. Because this report considers EMA regulation, only European agencies were included. The inclusion of England, Scotland, Belgium, France and the Netherlands was an unsystematic selec-tion.

research questions

oncology drugs licenced under exceptional circumstances

Belgium, England, France, the Netherlands and Scotland were included


10 LBI-HTA | 2013

Search strategy

For the overview of the additional clinical evidence a MEDLINE-search was performed via Pubmed for all clinical studies concerning the original licenced indication. The search terms were the name of the product and the indica-tion. Unpublished studies were identified through regulatory documents from EMA and the trial registry clinicaltrials.gov. Reimbursement documents were retrieved from the websites of the assessing agencies.

Data extraction

Information on the name of the active substance, date of approval, initial in-dication, the clinical data of the pivotal studies, the risk-benefit assessment by the CHMP and additional requirements for the marketing authorisation holder was extracted from the EPAR. For the overview of the additional evi-dence information was extracted on the type of study, indication, number of patients and for two products also the main outcome. For the analysis of the reimbursement assessments, the main remarks on the effectiveness, safety, cost-effectiveness, budget impact, severity of disease and ease of use were ex-tracted as well as the conditions to the reimbursement, including patient ac-cess schemes, and the final recommendation.

main sources: EMA, MEDLINE,

clinicaltrials.gov and reimbursement agencies

LBI-HTA | 2013 11

2 Background

This chapter gives an overview of all the relevant regulations and policies, additional information on reimbursement strategies, information on the se-lected reimbursement agencies and an introduction to the financing of on-cology drugs.

2.1 EMA

2.1.1 Authorisation procedures for medicinal products in the European Union

The European system offers several routes for introducing a medicinal prod-uct to the European market.

The Centralised Procedure allows for authorisation of medicinal products to the entire market of the European Community through a single application and evaluation by the EMA [12]. Within the EMA, the CHMP is responsible for preparing the Agency’s opinions on all questions concerning medicines for human use. The procedure is laid down in Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 [1].

The centralised procedure is mandatory for all medicinal products derived from biotechnology, designated orphan products and new actives substances intended for the treatment of acquired immune deficiency syndrome, cancer, neurodegenerative disorders, diabetes, auto-immune diseases, immune dys-functions and viral diseases. The procedure is optional for other new active substances and medicinal products that constitute a significant therapeutic, scientific or technical innovation. Generic applications for active substances that have already been authorised via the centralised procedure have au-tomatic access to the centralised procedure.

After applicants have notified the EMA of their intention to submit an ap-plication, a Rapporteur and Co-Rapporteur are appointed from amongst the members of the CHMP. The role of the Rapporteur is to perform the scien-tific evaluation and to prepare an assessment report to the CHMP. This as-sessment report receives comments from other CHMP members which are incorporated into the report and communicated to the applicant. After sub-mitting the applicants’ replies to the CHMP for discussion, the Rapporteur and Co-Rapporteur prepare a final assessment report. The CHMP then gives a favourable or unfavourable opinion as to whether to grant the authorisation. The time limit for this procedure is 210 days, with the possibility for the ap-plicant to apply for an accelerated assessment of max 150 days, when it con-cerns a product of major public health interest. The decision is ultimately made by the European Commission. A European Public Assessment Report (EPAR) will be published when the Commission issues its decision. When the decision is negative, a “Refusal EPAR” is published.

centralised Procedure laid down in Regulation (EC) No 726/2004

centralised procedure is mandatory for orphan drugs and innovative oncologic drugs


12 LBI-HTA | 2013

Under normal circumstances, the marketing authorisation is valid for five years. After five years the CHMP re-evaluates the benefit-risk balance of the product. When the marketing authorisation gets renewed, it will be valid for an unlimited period, unless otherwise specified.

There are other options for gaining marketing authorisation in the European Communion. The mutual recognition procedure is intended for products that have already got authorisation in one of the Member States, which will be recognised by other Member States. The decentralised procedure is like the mutual recognition procedure, also based on recognition by national authori-ties of a first assessment performed by one Member State. The difference is that it applies to medicinal products which have not received a marketing authorisation in any European member state at the time of application. Also national authorisations are still available for medicinal products to be mar-keted in one Member State only, when the centralised procedure is not man-datory.

2.1.2 Orphan Medicinal Product Designation

Orphan drug regulation is not a European invention. The Orphan Drug Act (ODA) from 1983 is said to be one of the most successful United States legis-lative actions in recent history [13]. Similar regulations came into force in Singapore (1991), Japan (1993), Taiwan and Australia (1998) and lastly in the EU (2000) [14]. The European parliament and the Council of Europe have adopted the regulation (EC) No 141/2000 of 16 December 1999 on orphan medicinal products, with the intention to stimulate research, development and bringing to the market of medications for rare conditions [1]. This regu-lation gives developers of medicinal products the opportunity to apply for orphan designation for their product, providing them with various advan-tages in the field of protocol assistance, access to the Centralised Procedure and marketing exclusivity.

In the EU, medicinal products are eligible for orphan designation if it is in-tended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition affecting not more than 5 in 10,000 people in the European Community at the time of the application or if it is unlikely that without incentives the marketing of the medicinal product would gen-erate sufficient return to justify the necessary investment. Additionally there needs to be an absence of alternatives and if such an alternative does exist, the medicinal product needs to be of significant benefit to the people affected by the condition [1].

An application for orphan designation can be submitted any time before the application for marketing authorisation is made. The Committee for Orphan Medicinal Products is responsible for examining the applications. Designated medicinal products are entered in the Community Register of Orphan Me-dicinal Products. The sponsor has to report to the EMA on the state of de-velopment of the product on a yearly basis. Designated products can be re-moved from the register for three reasons: 1) at request of the sponsor, 2) if it is established that the criteria for designation are no longer met or 3) at the end of the period of market exclusivity.

a normal marketing authorisation is valid for

five years

beside the centralised procedure there is the

mutual recognition procedure and the

decentralised procedure

orphan drug regulation has been implemented

in 2000 in Europe

a condition is ‘orphan’ when not more than 5 in 10,000 people in the EU

are affected

orphan designation is assigned by the

Committee for Orphan Medicinal Products

Background

LBI-HTA | 2013 13

The developer of a designated product may request protocol assistance in the development of the product before marketing authorisation and can apply for various fee reductions on protocol assistance, pre-authorisation inspec-tions, the initial application, post authorisation applications and the first an-nual fee. Most importantly however, the sponsor can get market exclusivity for 10 years, wherein no similar medicinal product for the same therapeutic indication shall be granted marketing authorisation. Exceptions can be made when either the holder of the original marketing authorisation has given his consent or is unable to supply the product in sufficient amounts or the sec-ond medicinal product is clinically superior. The market exclusivity can also be reduced to six years, if at the end of the fifth year is established that original designation criteria are no longer met.

2.1.3 Applications in exceptional circumstances

The procedure for granting a marketing authorisation under exceptional cir-cumstances is outlined in a guideline published by EMA [2]. A marketing authorisation may be granted under exceptional circumstances when an ap-plicant for marketing authorisation is unable to provide comprehensive data on the efficacy and safety under normal conditions of use because of one of the following reasons:

b the indication is too rare;

b the present state of scientific knowledge needed to provide comprehensive information is insufficient;

b it would be unethical to collect such information.

Once exceptional circumstances are granted, the applicant may be subjected to specific obligations such as additional efficacy or safety studies, there may be restrictions on the setting in which the product is used (e.g. inpatient or outpatient) and there may be additional requirements to the package leaflet and medical information of the product.

Marketing authorisations under exceptional circumstances are reviewed on an annual basis to reassess the risk-benefit balance. The fulfilment of the specific obligations concerning the provision of additional efficacy or safety data will normally not lead to the completion of a full dossier and a normal marketing authorisation. If it is expected that the applicant can confirm the positive benefit/risk balance with a full dossier in the future, the product could be authorised under conditional approval. This temporary authorisa-tion is also assessed annually and is not intended to remain conditional. Or-phan designation criteria are independent from the criteria to be considered for approval under exceptional circumstances [2].

the benefits for the developer are protocol assistance, fee reductions and 10 year market exclusivity

exceptional circumstances can be granted when the collection of comprehensive efficacy and safety date is impossible

the indication is too rare, the present state of scientific knowledge is insufficient or it would be unethical

risk/benefit reviewed on a yearly basis


14 LBI-HTA | 2013

2.1.4 Conditional approval

Medicinal products are eligible for conditional approval by the EMA if they belong to one of the three following categories:

b medicinal products which aim at the treatment, the prevention or the medical diagnosis of seriously debilitating diseases or life-threatening diseases;

b medicinal products to be used in emergency situations, in response to public threats duly recognised either by the WHO or by the Commu-nity in the framework of Decision (EC) No 2119/98;

b medicinal products designated as orphan medicinal products in ac-cordance with Article 3 of Regulation (EC) No 141/2000.

Additionally they have to meet all of the following requirements:

b the risk-benefit balance of the medicinal product is positive;

b it is likely that the applicant will be in a position to provide the com-prehensive clinical data;

b unmet medical needs will be fulfilled;

b the benefit to public health of the immediate availability on the mar-ket of the medicinal product concerned outweighs the risk inherent in the fact that additional data are still required.

Conditional marketing authorisations are valid for one year and can be re-newed. As with exceptional circumstances, specific obligations may be im-posed in relation to the collection of data. The main difference is that the authorisation is not intended to remain conditional.

Before conditional approval was introduced in 2006, authorisations that should have fallen into this category were authorised under exceptional cir-cumstances. Therefore a lot of drugs that were initially authorised under ex-ceptional circumstances now have a regular marketing authorisation [15].

2.2 Reimbursement aspects

2.2.1 Healthcare systems introduction

There is a variety in the way healthcare systems are organized in Europe. Most countries have either a national health service (England and Scotland) or an insurance-based healthcare system (Belgium, France and the Nether-lands. The insurance-based systems can be either ‘social’ or ‘private’ [16].

Social insurance-based healthcare systems rely on the principle of solidarity in population coverage, funding and benefits package. They have the impor-tant commonalities that the contributions are risk independent, i.e. they are not linked to health status, and they are transparently collected independent from state general revenues [17]. Private insurance-based healthcare systems, like in the United States of America, are not common in Europe. The ones that do exist work under social conditions, which means acceptance is man-datory (the Netherlands). However, in almost all European member states it is possible to buy additional private insurance [16].

conditional approval is possible when the

risk-benefit balance is positive, but part of the

clinical data is still awaited

a high medical need must be met

valid for one year

introduced in 2006

european countries mostly have a national

health service or an insurance-based

healthcare system

insurance-based systems can be social or private

and are funded by premiums

Background

LBI-HTA | 2013 15

A national health service is primarily funded through general taxation ra-ther than requiring insurance payments. Table 2.2-1 lists an overview of the main characteristics of the countries included in the report.

2.2.2 Reimbursement and financing aspects

Reimbursement of pharmaceuticals for outpatient use is often established in a positive list; a legally binding index of pharmaceuticals that are reim-bursed by the national health service/health insurance system. A negative list is also a possibility, in which case certain pharmaceuticals are specifically excluded from reimbursement/funding. Belgium, France and the Nether-lands work with a positive outpatient list. England and Scotland work with a negative list. For inpatient use, national lists of pharmaceuticals are less common, but Belgium and France have a positive list for inpatient pharma-ceuticals. England and Scotland have a negative list for inpatient pharma-ceuticals [16].

Co-payments on pharmaceuticals are common in almost all healthcare sys-tems, but differ in quantity and form. They can be found in the form of fixed-fees, prescription-fees, percentages of the price of the pharmaceutical or the difference between the list price and the retail price (see Table 2.2-1).

Oncology drugs are dispensed and administered in both the inpatient and outpatient setting. Some of them are suitable for self-administration, mainly those that can be taken orally or certain injectable dosage forms, and they can be dispensed by community pharmacies. Other dosage forms, like intra-venous infusions, are mainly administered in a clinical setting, often the hospital. The setting in which the drugs are used is in most countries of in-fluence on the way they are financed.

Table 2.2-2 show an overview of the agencies and institutes involved in re-imbursement assessments and decisions in the selected countries.

Belgium

The healthcare system in Belgium is a social insurance-based system and it’s for the largest part funded from health insurance contributions, general tax-ation and co-payments. In Belgium, co-payments on outpatient pharmaceu-ticals are common, but on life-saving drugs there is no co-payment. For in-patient drugs patients pay € 0,62 per hospitalisation day [18].

Reimbursement assessments are performed by the National Institute for Sickness and Invalidity Insurance (RIZIV). They are initiated by an applica-tion from the manufacturer. The assessment is based on the therapeutic val-ue, which includes effectiveness, safety, applicability and ease of use, price, medical need, budget impact and cost-effectiveness. On the basis of the ad-vice from RIZIV, the Ministry of Social Affairs will make a reimbursement decision. Since Belgium works with a positive list for both in- and outpatient pharmaceuticals, only evaluated pharmaceuticals are eligible for reimburse-ment [16].

a national health service is funded through general taxation

reimbursement of pharmaceuticals is generally established in positive or negative lists

co-payments are common in most EU countries

oncologic drugs are used in both the inpatient and outpatient setting

in Belgium there is no co-payment on life-saving drugs, like oncologic drugs

the reimbursement assessment in Belgium is performed by National Institute for Sickness and Invalidity Insurance


16 LBI-HTA | 2013

England

The National Health Service in the United Kingdom is a publicly funded health system. Although it is funded from national taxation, the National Health Service (England), the Health and Social Care in Northern Ireland (HSENI), the NHS Scotland and the NHS Wales are managed separately. The NHS England is divided into 10 Strategic Health Authorities, which supervise all NHS trusts in their respective area. The primary care trusts are local organisations in charge of primary care and control 80 % of the NHS budget. They allocate the budgets to the hospitals [19].

The National Institute for Health and Clinical Excellence (NICE) was set up in 1999 to reduce variation in the availability and quality of NHS treatments and care. NICE develops evidence-based guidelines on diagnosing, treatment and prevention [20].The Centre for Health Technology Evaluation (CHTE), within NICE, develops single technology appraisals, which are recommen-dations on the use of new and existing medicines and treatments within the NHS. The development of a single technology appraisal is quite an extensive process. The topics are referred to NICE by the Department of Health. Then evidence is gathered from both the manufacturer and independent consultees. The evidence is reviewed by an independent academic centre after which clinical experts, patients and carers can comment on it. The appraisal com-mittee then produces its final appraisal determination with recommendations on how the technology should be used in the NHS in England and Wales. Within this process there are several moments for stakeholders, such as the manufacturer and patient representatives, to comment, discuss or appeal. Once finalised, the advice issued by NICE is binding for the primary care trusts and funding has to be available within three months [21].

NICE maintains a strict maximum ICER of £ 30,000 per QALY gained when recommending technologies, but has the option to make exemptions for life-extending, end of life treatments. The three main criteria that are to be satis-fied are 1) the treatment is indicated for patients with a short life expec-tancy, normally less than 24 months and; 2) there is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared to current NHS treatment and; 3) the treat-ment is licensed or otherwise indicated, for small patient populations [22].

France

After market authorisation of a pharmaceutical, the Transparency Committee of the Haute Authorité de Santé (HAS) evaluates the medical benefit (Service Médical Rendu, SMR) and the improvement in medical benefit (Améliora-tion du Service Médical Rendu, ASMR). The SMR is a three point scale rang-ing from SMR I; pharmaceutical of major therapeutic value to SMR III; pharmaceutical of insufficient therapeutic value and the ASMR is a six point scale ranging from ASMR I; significant therapeutic value to ASMR VI; nega-tive opinion regarding inclusion into reimbursement. Subsequently the Trans-parency Committee advices on inclusion on one or both of the positive lists; the outpatient list (la liste des medicaments remboursable sagrées aux assu-rés sociaux) and the inpatient list (la listedes médicaments agrées aux collec-tivités). The SMR determines the rate of reimbursement; 100 %, 65 % or 35 %. The reimbursement rate for cancer treatment is always 100 %. Inpatient pharmaceuticals are financed through a diagnosis related group-type system. Additionally there is the T2A-list of innovative and expensive pharmaceuti-cals, that are financed separately [23].

the national health services in England,

Wales, Scotland and Northern Ireland are separately managed

in England the National Institute for Health and

Clinical Excellence performs health

technology assessments

NICE maintains a strict maximum ICER of £ 30,000 per QALY, but exceptions are made for

life-extending, end of life treatments

reimbursement assessments in France are performed by the

Transparency Committee of the Haute Authorite´

de Sante´

Background

LBI-HTA | 2013 17

The Netherlands

The reimbursement evaluation of pharmaceuticals is generally initiated by an application by the marketing authorization holder to the minister of Health, Welfare and Sports (VWS). The minister is assisted in her decision by the Healthcare Insurance Board (CVZ). Within the CVZ, the Committee Pharmaceutical Aid (CFH) will draw up an ‘assessment of therapeutic value’ and make a budget impact estimate. For new chemical entities, the CFH will also give an opinion on the justification of the efficiency (cost-effec-tiveness). The therapeutic value of a pharmaceutical is based on five criteria: positive effects, negative effects, experience with the drug, applicability and ease of use. The weight of these criteria is carefully determined in each case. Costs play no role in the assessment of therapeutic value. Based on the re-port from the CFH, the appraisal committee gives its opinion on the four principles of the benefits of Dutch basic health insurance, necessity (disease burden), effectiveness, cost-effectiveness and practicability. Based on the CFH and the appraisal committee reports, the CVZ issues an advice to the minister, who makes the ultimate decision to designate a pharmaceutical for reimbursement by the insurance companies [24].

Inpatient pharmaceuticals are not reimbursed by the health insurers, but are paid from the hospital budget. To counteract the so-called ‘postcode pre-scribing’ (expensive pharmaceuticals only being available in certain regions or hospitals), two policies were introduced in 2006 to provide additional funding for really expensive innovative drugs (costs of at least 2,5 million Euros per drug per hospital per year) and orphan drugs (when the yearly costs of the drug exceed 5 % of the total drug budget). Applications for this funding cannot be made by the manufacturer, but have to be made by par-ties like the clinicians organizations. Additionally, the funding is always conditional. After four years, the drug is reassessed on budget-impact, thera-peutic value and cost-effectiveness. A dossier for this assessment has to be submitted by the party that originally applied for the funding, but the nec-essary research is a joint responsibility of the manufacturer, clinicians and the healthcare institutes. As of 2012 these two policies are no longer active. Funding for these drugs is now included in the hospital budgets again. The evaluation process however, has not been changed [25-27].

Scotland

In Scotland the Scottish Medicines Consortium (SMC) evaluates all newly licenced pharmaceuticals on the basis of a dossier submitted by the manu-facturer. If the manufacturer decides not to submit a dossier, the SMC will not recommend a drug. The assessment performed by the SMC is based on the effectiveness, safety, target population, costs and cost-effectiveness. If the SMC recommends a pharmaceutical, local NHS boards have to decide if they want to include it into their local formulary. The NHS Quality Improvement Scotland considers if the advice given by NICE is relevant to patients in Scotland. If so, they publish the advice on their websites and the local NHS boards have to consider it for their local formularies [28].

in the Netherlands reimbursement evaluations are performed by the Healthcare Insurance Board

inpatient pharmaceuticals are paid from the hospital budget but additional funding is available for orphan and very expensive drugs

in Scotland the Scottish Medicines Consortium evaluates al newly licenced drugs

Marketing A

uthorisations under Exceptional Circumstances for O

ncology Drugs

18 LBI-H

TA | 2013

Table 2.2-1: Main characteristics of the healthcare systems and reimbursement of pharmaceuticals of the countries included in the report

Belgium England France The Netherlands Scotland

Type of healthcare system Insurance-based National health service Insurance-based Insurance-based National health service

Health insurance is mandatory Yes NA Yes Yes NA

Social insurance Yes No Yes No No

Private insurance is the main type No No No Yes No

Reimbursement list

Type of list outpatient pharmaceuticals Positive Negative Positive Positive Negative

Type of list inpatient pharmaceuticals Positive Negative Positive NA Negative

Co-payments outpatient pharmaceuticals

% of the price X X

Fixed fee X

Payment of difference between reference price and retail price X X

Prescription fee X

Deductible X

Annual co-payment ceiling X

Source: Kleijnen et al, 2011 [16]

Abbreveations: NA – Not applicable

Background

LBI-HTA | 2013

19

Table 2.2-2: Agencies and organisations involved in reimbursement decisions in the countries included in the report

Belgium England France The Netherlands Scotland

Reimbursement evaluations

Always, inpatient and outpatient

Always for branded, oncology an autoimmune disease, sometimes for generics and orphan

Always for branded, oncology, autoimmune and orphan, sometimes generics

Yes, not for generics, sometimes for inpatient use

Always for oncology, autoimmune and orphan, sometimes for branded, never for generics

Agency that performs the assessment

INAMI/RIZIV (Institut national d’assurance maladie-invalidite´/ RijksInstituut voor Ziekte – en Invaliditeits Verzekering)

Product sponsor/ academic group (rapid) academic group/ stakeholders (full)

Haute Autorite´ de Sante´ (HAS) (French National Authority for Health)

Health Care Insurance Board (CVZ)

Scottish Medicines Consortium (SMC)

Organisation that provides advice for the decision

INAMI/RIZIV National Institute for Health and Clinical Excellence (NICE)

HAS CVZ SMC

Organisation that makes the decision

Ministry of Social Affairs NICE/NHS primary care trust

Ministry of Health and Social Affairs

Ministry of Health, Welfare and Sport (VWS)

Regional Health Authority

Source: Kleijnen et al, 2011 [16]


20 LBI-HTA | 2013

2.2.3 Patient Access Schemes

Where reimbursement decisions traditionally only focused on whether to pay for a product, for the entire indication, or for a particular subgroup, recently a number of new ways to finance pharmaceuticals have been introduced, so called patient access schemes. These schemes can be classified in different ways which are discussed below [29, 30].

Coverage with evidence development

Coverage with evidence development (CED) can be divided into ‘only with research’ where all patients are given access to the treatment, but evidence is also generated, an ‘only in research’ where the treatment is only paid for pa-tients involved in the research. These types of schemes are particularly use-ful for treatments that appear promising, but may not yet have the required supporting evidence [29, 30]. The generating of additional evidence can take place in various settings. The marketing authorisation holder is not always the sole responsible party, but also patient organizations and scientific bodies can have interests in additional clinical evidence and proof of cost-effective-ness, as it can assist in more adequate use of resources. CED has been stan-dard practice for expensive or orphan, inpatient pharmaceuticals in the Neth-erlands since 2006, with varying results.

Conditional treatment continuation

In conditional treatment continuation (CTC) a treatment will only continue to be reimbursed when a short-term target clinical effect is reached. These schemes require the existence of a short-term measure that is an acceptable surrogate for relevant clinical endpoints. CTC is particularly useful when doctors and patients are inclined to continue treatment merely because of a lack of alternatives [29]. An example of such a reimbursement scheme is the agreement between Johnson and Johnson and the UK’s NHS. Bortezomib, used in the treatment of progressive multiple myeloma, is only continued in people who have a complete or partial response, measured by serum M pro-tein, after a maximum of four cycles. Johnson and Johnson rebates the full cost of bortezomib for people who have less than a partial response [31].

Performance linked reimbursement

When the generation of more evidence is very expensive, but the manufac-turer has sufficient confidence in its product or when a therapy is clearly ef-fective in certain patients, but cost-effectiveness criteria are not reached, a performance-linked reimbursement scheme can be appropriate. The major-ity of performance-linked reimbursement schemes involve rebates or refunds when a certain treatment goal is not reached [29]. A recent example of such a scheme is the pay-for-performance agreements of August 2012 between hospi-tals in the Netherlands and Novartis, for the drug omalizumab (Xolair), used in the treatment of severe asthma. Novartis has agreed to pay for the treat-ment of patients with omalizumab that turns out to be unsuccessful. The Dutch association of physicians for pulmonary disease is responsible for the inclusion and evaluation criteria of the patients and the hospital pharmacy is responsible for reclaiming the costs of omalizumab in case of an unsuccess-ful treatment. For the Netherlands, this is the first pay-for-performance re-imbursement scheme and therefore it will initially last for two years [32].

coverage with evidence development can be divided into ‚only in

research’ and ‚only with research’

conditional treatment continuation is related

to short-term target clinical effects

performance linked reimbursement is

dependent on a certain treatment goal

Background

LBI-HTA | 2013 21

Non-outcome-based schemes

Additional to these health-outcomes-based schemes, there are multiple non-outcome-based schemes, where effective prices can be determined on a pa-tient or population level. An example of a patient level scheme is the dis-count on treatment initiation with sunitinib in renal cell carcinoma. The manufacturer of sunitinib (Pfizer) has agreed a patient access scheme with the Department of Health, in which the first treatment cycle of treatment is free to the NHS [33]. A fixed cost per patient is agreed between the manu-facturer of gefitinib (Astra Zeneca) and the Department of Health. Gefitinib for first-line treatment of non-small cell lung cancer will be available at a single fixed cost of £ 12,200 per patient irrespective of the duration of treat-ment. On top of that the manufacturer will not invoice the NHS until the third monthly pack of gefitinib is supplied. This means that treatment that lasts less than 3 months will not be charged by the manufacturer [34]. Popu-lation level schemes include discounts for payers on the list price, total ex-penditure caps and price/volume agreements [30].

non-health outcome – based schemes include discounts, fixed costs per patient and price/ volume agreements

22 LBI-HTA | 2013

3 Results

3.1 Oncology drugs under exceptional circumstances

The search on the EMA website yielded that there are currently only four oncologic drugs authorised under exceptional circumstances; nelarabine, clo-farabine, histamine dihydrochloride and trabectedin (Table 3.2-1). Seven other oncologic drugs have previously been authorised under exceptional circumstances, but later received a normal licence, with six being still on the market. (Alemtuzumab has been withdrawn for commercial reasons.)

3.2 Clofarabine – Evoltra

3.2.1 Indication

Acute lymphoblastic leukaemia (ALL) is a cancer of the blood and bone mar-row, in which too many immature lymphocytes are produced. Blood stem cells produced in the bone marrow can develop in either a myeloid stem cell or a lymphoid stem cell. Myeloid stem cells can develop in three types of mature blood cells; red blood cells, blood platelets or granulocytes. Lym-phoid stem cells develop via lymphoblasts into T-lymphocytes, B-lympho-cytes or natural killer cells. In ALL too many lymphoblasts, T-lymphocytes or B-lymphocytes are produced. These immature cells are not only unable to fight infections properly, their large amounts are also displacing the healthy blood cells, which may lead to infection, anaemia and blood coagulation dis-orders [35].

The overall incidence rate in Europe of leukaemia in children aged 0-14 years was 44 per million person-years during 1988-1997. Lymphoid leukae-mia (LL), which mostly consists of ALL, accounts for around 81 % of leu-kaemia [36]. Orphanet estimates the prevalence of ALL on 8.1/100,000 [37].

There are multiple kinds of prognostic factors that can predict the outcome of treatment. Clinical features like age and leukocyte count at diagnosis are strong prognostic factors in patients with B-cell precursor ALL. Secondly, the genetics of the leukaemia cells play an important part in risk stratifica-tion. Thirdly, the patient’s pharmacokinetics and pharmacodynamics are of influence on treatment response. Early response to treatment, influenced by all three features, is consequently the most powerful predictor of outcome. The measurement of minimal residual disease, which is the presence of leu-kaemic cells below the threshold of detection by conventional morphologic methods, with the use of either flow cytometry or polymerase-chain-reaction, can therefore be an important guide in post-induction treatment [38, 39].

four oncologic drugs are currently licenced under

exceptional circumstances

acute lymphoblastic leukaemia is a cancer of

the blood and bone marrow

prevalence estimated at 8.1/100,000

important prognostic factors are leukocyte

count, genetics of the leukaemia cells and

patients PD/PK

Results

LBI-HTA | 2013

23

Table 3.2-1: Oncology drugs authorised under exceptional circumstances by the EMA

International Nonproprietary Name Brand Name

Authorisation date Original licenced indication

Date of regular marketing authorisation

docetaxel Taxotere 27.11.1995 Second line monotherapeutic treatment of patients with advanced breast cancer after anthracycline failure

07.07.1998

alemtuzumab MabCampath 06.07.2001 Treatment of patients with B-cell chronic lymphocytic leukaemia (BCLL) for whom fludarabine combination chemotherapy is not appropriate.

04.07.2008

temoporfin Foscan 24.10.2001 Palliative treatment of patients with advanced head and neck squamous cell carcinoma failing prior therapies and unsuitable for radiotherapy, surgery or systemic chemotherapy.

21.05.2008

imatinib Glivec 07.11.2001 Adult patients with Philadelphia chromosome (bcr-abl) positive chronic myeloid leukaemia (CML) in chronic phase after failure of interferon- alpha therapy, or in accelerated phase or myeloid blast crisis

13.04.2007

arsenictrioxide Trisenox 05.03.2002 Induction of remission and consolidation in adult patients with relapsed/refractory acute promyelocytic leukaemia (APL), characterised by the presence of the t(15;17) translocation and/or the presence of the pro-myelocytic leukaemia/retinoic-acid-receptor alpha (PML/RAR-alpha) gene. Previous treatments hould have included a retinoid and chemotherapy.

10.08.2010

ibritumomabtiuxetan Zevalin 16.01.2004 Treatment of adult patients with rituximab relapsed or refractory CD20+ follicular B-cell non-Hodgkin’s lymphoma (NHL).

22.05.2008

bortezomib Velcade 26.04.2004 Treatment of patients with multiple myeloma who have received at least two prior therapies and have demonstrated disease progression on the last therapy

19.03.2012

clofarabine Evoltra 29.05.2006 Treatment of acute lymphoblastic leukaemia (ALL) in paediatric patients who have relapsed or are refractory after receiving at least two prior regimens and where there is no other treatment option anticipated to result in a durable response.

–

nelarabine Atriance 22.08.2007 Treatment of patients with T-cell acute lymphoblastic leukaemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) whose disease has not responded to or has relapsed following treatment with at least two chemotherapy regimens.

–

trabectedin Yondelis 17.09.2007 Treatment of patients with advanced soft tissue sarcoma, after failure of anthracyclines and ifosfamide, or who are unsuited to receive these agents. Efficacy data are based mainly on liposarcoma and leiomyosarcoma patients.

–

histamine dihydrochloride

Ceplene 07.10.2008 Ceplene maintainance therapy is indicated for adult patients with acute myeloid leukaemia in first remission concomitantly treated with interleukin-2 (IL-2). The efficacy of Ceplene has not been fully demonstrated in patients older than age 60.

–


24 LBI-HTA | 2013

Treatment

Treatment schedules in ALL are adapted to phenotype, genotype and risk of the disease subtype. Except for mature B-cell ALL, all subtypes are treated with both remission-induction therapy followed by intensification (or consoli-dation) therapy. Allogeneic hematopoietic stem-cell transplantation (HSCT) is not always indicated. Remission-induction therapy aims at reducing the amount of leukaemia cells to 1 % or less of the initial burden. It usually con-sist of three or four different drugs; vincristine, a corticosteroid, L-aspara-ginase and/or anthracycline [35, 38]. Remission-induction, when successful, is followed by treatment intensification. These treatment schedules can largely vary between studies and populations, but in childhood ALL high-dose meth-otrexate, cytarabine, mercaptopurine and high-dose asparaginase are com-monly used. Maintenance treatment follows for another two to three years, consisting usually of weekly methotrexate and daily mercaptopurine, poten-tially supplemented with other agents.

To clear leukaemic cells from the central nervous system (CNS) and to pre-vent CNS-relapse, CNS-directed therapy is given to all patients with ALL. This can either exist of intrathecal therapy, CNS-penetrant chemotherapy or cranial radiation. CNS-treatment is also adapted to the risk profile of the pa-tient [35, 38,39].

Relapse

Complete remission (CR) is reached in >95 % in children and in 60-80 % in adults. Approximately 25-30 % of children relapse or are refractory to initial therapy. Relapse within 6 months results in a 10-20 % chance of long-term survival, whereas relapse over one year after completion of initial therapy re-sults in a slightly better outlook with cure rates of 30-40 % [40, 41].

Patients in second remission still have a poor outcome and are therefore rec-ommended for an allogeneic bone marrow transplantation (BMT), stem cell transplantation (SCT) or autologous transplantation. For patients in second relapse, who would normally have received at least two multi-agent chemo-therapy regimens, all established treatment options would have been ex-hausted [41].

3.2.2 Mechanism of action

Clofarabine is a nucleoside analogue anti-metabolite anticancer agent. Its cytotoxicity results from the inhibition of ribonucleotide reductase and DNA polymerase [42].

treated with r emission-induction

therapy followed by intensification

approximately 25-30 % of children relapse or

are refractory to initial therapy

for patients in second relapse all established

treatment options would have been exhausted

nucleoside analogue anti-metabolite

anticancer agent

Results

LBI-HTA | 2013 25

3.2.3 Summary of licensing documents

Clofarabine was approved by the EMA on 29 May 2006 for the treatment of paediatric patients with relapsed or refractory ALL after receiving at least two prior regimens and where there is no other treatment option anticipated to result in a durable response.

Efficacy

The demonstration of efficacy was based on one pivotal phase II study (CLO-212) [41]. Due to the limited number of patients in second relapse, no exten-sive clinical development program was conducted. Study CLO-212 was an open label, non-randomised, single-arm study in paediatric patients with ALL in second or subsequent relapse and/or refractory, who were ≤21 years of age at time of initial diagnosis. The primary efficacy endpoint in this study was the number of patients to achieve disease remission, categorised into complete remission (CR)defined as bone marrow blast counts ≤5 %, no evidence of disease and full recovery of peripheral blood counts. CRp was defined as complete response without full haematologic recovery and partial remission (PR)was defined as complete disappearance of circulating blasts and bone marrow blast counts ≤25 %. Overall 61 patients, with a median age of 12 years (range 1-20 years) were included in the study. Eighteen out of the 61 patients (30 %) achieved a CR, CRp or PR. Twelve 12 of these 18 pa-tients achieved a CR or CRp (20 %). A total of 10 children underwent HSCT, including 8 out of the18 patients who had achieved a response. None of the responsive patients had any clofarabine-related or clinically significant tox-icity that would have prevented HSCT.

Median survival for all patients was 12.9 weeks and greater than one year for patients who had responded to treatment. Although historical data are diffi-cult to interpret, the EPAR states that data from Dutch and German cancer registries indicate that patients with multiply relapsed ALL have an esti-mated median survival of 9-10 weeks without further intervention.

Safety

The safety data in the application to the EMA were based on 132 paediatric patients (1-21 yrs) with either ALL or acute myeloid leukaemia (AML) who took part in one of several phase I or phase II studies [41]. According to the EPAR, the interpretation of safety data in uncontrolled studies is difficult though, because most patients are heavily pre-treated and might already suf-fer from on-going toxicity. The most frequently reported drug-related ad-verse events were nausea (61 %), vomiting (61 %), febrile neutropenia (32 %), headache (24 %), pyrexia (21 %), pruritus (21 %) and dermatitis (20 %). Se-rious adverse events related to treatment with clofarabine were reported in 58 % of the patients, but only 2 patients discontinued treatment due to an adverse event. Four deaths during the trials were considered by the investi-gators to be related to clofarabine. During the clinical trials with clofara-bine, six cases of systemic inflammatory response syndrome/capillary leak syndrome were reported. Other risks associated with clofarabine are hepatic and cardiac toxicity and potentially renal toxicity. Important missing in-formation is the safety of use for more than 3 cycles.

one pivotal phase II study in 61 paediatric patients

safety data based on 132 patients


26 LBI-HTA | 2013

Risk/Benefit

The scientific discussion of the EPAR states that although an application would normally require data generated by randomised, controlled trials, the lack of it was justified by the small size of the population of patients in sec-ond relapse. The facilitating of HSCT by a partial or complete remission was considered a meaningful, clinical effect that may have an impact on dura-tion of survival. The uncertainties regarding the safety profile of clofarabine were considered justified in view of the small size of the population of pa-tients, but additional pharmacovigilance activities were considered neces-sary.

Specific obligations to be fulfilled by the marketing authorisation holder

Outside of the risk management plan submitted by the manufacturer, the CHMP required additional risk minimisation activities in the form of a user’s information package, to inform prescribers on the safe use of the drug, and the setup and promotion of a voluntary adverse event reporting system [41]. During the 3rd annually reassessment, additional obligations have been added [43]. The manufacturer was requested to supply population pharmacokinet-ics data and data to support the recommendation of dose adjustments in pa-tients with moderate renal impairments. In the monitoring of adverse effects, extra attention was to be given to the monitoring of veno-occlusive disease after HSCT.

3.2.4 Additional publications

Table 3.2-3 presents an overview of all published trials and case reports of single-agent clofarabine in patients with ALL. A search of the literature yielded just five additional publications outside those mentioned in the EPAR, two retrospective reports and three case reports. One publication reports of five patients in the United Kingdom having been treated with single agent clofarabine outside of clinical trials [44]. Two of these 5 patients achieved a CR. Single agent therapy was only given during the early study period how-ever, patients received combination therapy later on. In a retrospective study by the Spanish PETHEMA group, 5 of 31 patients were treated with single agent clofarabine treatment, 1 achieved a CR [45].

During the application at the EMA, a second open-label phase II study of clofarabine in paediatric patients with refractory/relapsed ALL had already started in Europe [41]. The design of the study BIOV-111 was similar to the pivotal CLO-212 trial. BIOV-111 had been completed in 2007 and the results were presented to the EMA in 2008 and to the FDA in 2010, but have not been published. The BIOV-111 results are said to be consistent with the final results of CLO-212 [46, 47]. Of 65 paediatric patients included, 3 patients (4,6 %) achieved a CR, 12 patients (18,5 %) achieved a CRp and 1 patient (1,5 %) achieved a PR. Seven out of 71 treated patients went on to trans-plant.

lack of RCT justified by small size of the

population

specific obligations related to safety

measures and pharmacokinetic data

few reports of

single-agent use of clofarabine

additional trial performed by the

manufacture has not been published

Results

LBI-HTA | 2013 27

Table 3.2-2: Publications on clinical trials and case reports of single-agent use of clofarabine in patients with ALL

Source Study ID Journal Type of Study No. of Patients

(total/ALL) Age CR+CRiBarba et al, 2012 [45]

American Journal of Hematology

Retrospective 31 16-72 1/5*

O’Connor et al, 2011 [44]

British Journal of Haematology

Retrospective 23/5 0-17 2/5*

McGregor et al, 2009 [48]

Am J Hematol Case Report 3 19-49 2/3

Johnston et al, 2008 [49]

Pediatric Blood & Cancer

Case Report 1 10 0/1

Jeha et al, 2006 [50]#

CLO-212 J ClinOncol Phase II, open-label

61 1-20 12/61 (20 %)

Choi et al, 2006 [51]

Yale J BiolMed Case Report 1 35 1/1

Jeha et al, 2004 [52]#

ID99-383 Blood Phase I, dose-finding

25/17 1-19 7/17 (41 %)

Kantarjian et al, 2003 [53]#

ID00-038 Blood Phase II, open-label

62/12 19-82 2/12 (17 %)

Kantarjian et al, 2003 [54]#

DM93-036 J ClinOncol Phase I, dose-finding

51/13 >18 2/13 (15 %)

Genzyme [46, 47]

BIOV-111 Unpublished Phase II, open-label

65 <21 15/65 (23 %)

# ... Studies included in licencing application * .... In both studies, only five patients received single agent treatment.

3.2.5 Summary of reimbursement documents

Clofarabine has been assessed by RIZIV,HAS, CVZ and SMC and received a positive recommendation by all four agencies (Table 3.2-3). NICE has not assessed clofarabine. The amount of detail in the assessments varies between agencies.

RIZIV (Belgium) presented a very brief summary of efficacy and safety re-sults from the pivotal trial in their assessment of 1 July 2008 [55]. They ac-knowledged the absence of alternative treatment for this patient group and declared clofarabine eligible for reimbursement. They did however impose two additional restrictions; a maximum of three cycles are reimbursed per patient and refractory patients have to have tried at least three different regi-mens before starting clofarabine.

The Transparency Committee of HAS (France) issued an opinion on clofara-bine on 13 December 2006 [56]and based its assessment on data from stud-ies ID00-038 and CLO-212. They concluded that clofarabine significantly improves the treatment of ALL in relapsed or refractory children (ASMR II), despite the methodological limitations of the pivotal study.

CVZ (the Netherlands) determined the therapeutic value of clofarabine as compared to best supportive care in a report published on 24 September 2007 [57]. They based the evaluation on the product information and scien-tific discussion from the EPAR and the published result from studies ID99-383 [52] and CLO-212 [50]. They concluded that the results of treatment with clofarabine, short-term remission in about 25 % of the patients with the

RIZIV imposes restrictions on reimbursement

HAS recommends clofarabine for reimbursement

clofarabine is included in the Dutch orphan drug financing policy


28 LBI-HTA | 2013

possibility long term remission after HSCT, were considerably better than the results of best supportive care and therefore clofarabine was recommended within its registered indication. It was included in the orphan drug financ-ing policy.

SMC (Scotland) issued an advice on 8 December 2006 [58] and adopted the opinion of EMA that even though there were no randomised clinical trials, the effects of clofarabine in terms of remission and facilitating HSCT were considered clinically relevant. The economic analysis presented by the man-ufacturer however, showed that cost-effectiveness for clofarabine was highly dependent on patients receiving HSCT after treatment. The use of clofara-bine is therefore restricted to patients in whom it is being used to bridge to HSC.

Table 3.2-3: Main remarks on different aspects from the reimbursement evaluations of clofarabine

CVZ HAS RIZIV SMC Decision date 24.09.2007 13.12.2006 01.07.2008 08.12.2006 Effectiveness considerable

better than best supportive care

actual benefitis substantial

capable of inducing remission

remission and facilitating HSCT is clinically significant

Safety often severe side-effects, sometimes life-threatening

tolerance data are limited

list of AEs in trials important risks identified from EPAR

Cost-effectiveness – – – highly dependent on HSCT

Budget impact € 700,000 per year – € 639,180 per year £ 216,000 per yearSeverity of disease – – – – Easeofuse mentioned – mentioned – Recommended yes yes yes yes Conditions evidence

development max 3 cycles,

refractory patients after 3 prior regimens

only as a bridge to HSCT

Abbreviations: CVZ – College voor Zorgverzekeringen, HAS – Haute Autorité de Santé, RIZIV – Rijks Instituut voor Ziekte- en Invaliditeits Verzekering, SMC – Scottish Medicines Consortium, AE – adverse event, HSCT – Hematopoietic stem cell transplant, EPAR – European public assessment report

3.3 Nelarabine – Atriance

3.3.1 Indication

Lymphoblastic leukaemia (LBL) is considered the lymphomatous variant of ALL (see chapter Clofarabine). The abnormal lymphocytes are generally in the lymph nodes or thymus gland and the bone marrow is lesser involved (<25 % marrow blasts). LBL is a form of non-Hodgkin lymphoma, a large group of cancers of lymphocytes. Treatment strategies for T-ALL and T-LBL are often the same, with comparable results [35, 59].

SMC restricts clofarabine to patients

that are eligible for HSCT

lymphoblastic

leukaemia is considered the lymphomatous

variant of ALL

Results

LBI-HTA | 2013 29


Nelarabine is the water soluble prodrug of 9-beta-D-arabinofuranosyl gua-nine (ara-G), an antineoplastic agent that acts as DNA synthesis inhibitor. Ara-G is converted intracellularly to the active triphosphate ara-GTP, in both B-cells and T-cells. Due to a more rapid catabolism in B-cells, ara-G is selectively toxic to T-cells owing to a greater exposure to ara-GTP [60].


Nelarabine received its marketing authorisation under exceptional circum-stances on 22 August 2007. It is indicated for the treatment of patients with T-cell acute lymphoblastic leukaemia (T-ALL) and T-cell lymphoblastic lym-phoma (T-LBL) whose disease has not responded to or has relapsed follow-ing treatment with at least two chemotherapy regimens.

Efficacy

In the application to EMA, the applicant presented two pivotal phase II open-label studies, one in patients ≥16 years of age (Study ID PGAA2002) and one in patients ≤21 years of age (Study ID PGAA2001) [61].

Study PGAA2001 was a phase II, open-label, multicentre clinical trial which included paediatric patient ≤21 years of age at diagnosis with refractory or recurrent T-ALL or T-LBL. Nelarabine was administered at a dose ranging from 400 mg/m2 to 1200 mg/m2 as a one-hour infusion daily over five days, every three weeks. The objectives of the study were to evaluate the response rate i.e. complete response (CR) defined as bone marrow blast counts ≤5 %, no evidence of disease and full recovery of peripheral blood counts. CR* was defined as complete response without full haematologic recovery. Partial re-sponse (PR) was defined as bone marrow blast ≤25 %. Secondary outcome measures included duration of response and overall survival. Five out of 39 patients in second relapse achieved a CR and an additional four patients achieved a CR*. The median duration of response was 12,3 weeks. Four of the nine patients in CR or CR* received an SCT. The median overall sur-vival in patients in second relapse was thirteen weeks and the one-year sur-vival was 14 %.

Study PGAA2002 was a similar study in adult patients ≥16 years of age with relapsed or refractory T-ALL or T-LBL. Nelarabine was administered at a dosage of 1500 mg/m2 i.v. over 2 hours on days 1, 3, and 5 of a 21 day cycle. Objectives and outcomes were similar to study PGAA2001. Five out of 28 pa-tients with two or more prior inductions achieved a CR and one additional patient received a CR*. The duration of response in patients in second re-lapse ranged from four to 195,4+ weeks. The median overall survival was 20,6 weeks and the one-year survival 29 %.

Safety

The safety evaluation in the EPAR was based on 459 adult and paediatric patients enrolled in four phase I studies and three phase II studies. Neuro-logical toxicity was the dose-limiting toxicity and despite of an extensive phase I programme, early in the pivotal phase II trials additional dose-adjust-ments had to be made. In adult patients receiving the adjusted 1500 mg/m2

antineoplastic agent and DNA synthesis inhibitor

two pivotal phase II studies

one trial in adult patients and one trial in paediatric patients



30 LBI-HTA | 2013

dose, the safety profile in terms of haematological and gastrointestinal ef-fects was comparable to other cytotoxic agents. Neurological adverse events were reported in 8 % of the adult patients involved in phase II studies com-pared with 20 % in paediatric patients that received 650 mg/m2. Ninety-nine per cent of the paediatric patients in this dose group experienced haemato-logical toxicities. Among all the patients in the database, 13 % experienced a grade 3 neurological adverse event and 7 % a grade 4 neurological adverse event. The limited safety database resulted in specific post-marketing obli-gations.

Risk/Benefit

The EPAR states that although normally an application would require data generated by randomised, controlled trials, the lack of it was justified by the small size of the population of patients in second relapse. And even though it was not possible to compare the response rate with anything, the magni-tude was deemed clinically relevant because some patients were able to un-dergo a stem cell transplant. The uncertainties regarding the safety profile of nelarabine were considered justified in view of the small size of the popula-tion of patients, but additional pharmacovigilance activities were necessary.


The CHMP required the following specific obligations:

b To provide data from an on-going phase III Children’s Oncology Group study AALL0434, entitled “intensified methotrexate, nelara-bine and augmented Berlin-Frankfurt-Münster therapy for children and young adults with newly diagnosed T-cell ac ute lymphoblastic leukaemia”.

b To perform a post-marketing surveillance study for nelarabine in the indicated patient population under 21 years of age receiving the 650 mg/ m2 dose [62].


Table 3.3-1 presents an overview of all published trials and case reports of single-agent nelarabine in patients with ALL. A search of the literature yielded just six additional publications outside those mentioned in the EPAR, two clinical trials and four case reports. Two of the publications were in Ja-panese and could not be understood.

The single arm trial by Gökbuget et al [63]included thirteen patients in sec-ond relapse and reported a response rate of six complete remissions with or without full haematologic recovery. One-year survival however, was only 9 %. Information from clinicaltrials.gov indicates that nelarabine is currently being tested in several multi-agent regimens, in different clinical trials.

lack of RCT justified by small size of the

population

specific obligations related to safety

measures

two additional clinicaltrialspublished

Results

LBI-HTA | 2013 31

Table 3.3-1: Publications on clinical trials and case reports of single-agent use of nelarabine in patients with ALL

Source Study ID Journal Type of Study

No. of Patients

Age median (range)

CR+Cri [95 %CI]

Go¨kbuget et al, 2011 [63]

J Clin Oncol Phase II, single arm

Total=126 2nd relapse=13

33 (18-81)

CR 6/13 (46 %)

Horibe et al, 2011 [64]

PGA105446 Rinsho Ketsueki

Phase I

Papayannidis et al, 2010 [65]

Am J Hematol

Case report 1 30 CR, complete paraplegia

Iino et al, 2009 [66]

Rinsho Ketsueki

Case report

Sigalas et al, 2009 [67]

Leuk Res Case report 1 31 CR

Alvarado et al, 2007 [68]

Leuk Res Case report 1 48 CR

DeAngelo et al, 2007 [69]#

PGAA2002 Blood Phase II, single arm

Total=39, 2nd relapse=28

34 (16-66)

29 % [13 %, 49 %]

Berg et al, 2005 [70]#

PGAA2001 J Clin Oncol Phase II, single arm

Total=153, 2nd relapse=39*

10.8 (2.5-20)

23 % [11 %, 39 %]

Kurtzberg et al, 2005 [71]#

PGAA1001 J Clin Oncol Phase I, dose finding

Total=93, T-ALL/LBL=39

(3-75) CR 9/39 (23 %)

# ... Studies included in licencing application


Nelarabine has been assessed by HAS, RIZIV and SMC and all three have recommended nelarabine for reimbursement (Table 3.3-2).

In the decision document from 1 June 2008 [72], RIZIV presented a brief overview of the results from the pivotal study, the incidence of ALL/LBL in Belgium and an estimation of the budget impact. In their re-evaluation in November 2010, it became clear that there was hardly any new information available. To that date, only one patient per year had been treated with ne-larabine in Belgium.

The Transparency Committee of HAS issued an opinion on nelarabine on 19 December 2007 [73]. In their report they present a brief overview of the clin-ical efficacy and safety data from the two pivotal trials. They considered the efficacy/safety ratio of this product to be high and recognised the lack of al-ternative treatments in adult patients. Nelarabine was considered to provide a significant improvement in actual benefit (ASMR II), by facilitating access to an allograft in some patients. Therefore, nelarabine was recommended for reimbursement.

In their recommendation of 7 March 2008 SMC adopted the opinion of the EMA that the lack of randomised trials was justified in view of the small size of the population of patients in second relapse [74]. Additionally they ac-cepted the complete response rate as a reasonable surrogate for clinical bene-fit. They deemed the economic analysis provided by the manufacturer to be of good quality, but cost-effectiveness was highly depending on HSCT and the assumed prolonged survival after that procedure. Therefore the SMC ac-cepted the use of nelarabine only as a treatment to bridge to HSCT and not for palliation.

RIZIV recommends nelarabine

HAS emphasises the significant improvement in actual benefit

SMC restricts nelarabine to patients that are eligible for HSCT


32 LBI-HTA | 2013

Nelarabine was not evaluated by NICE. It was considered for a potential technology appraisal, but rejected in July 2007 [75]. CVZ also did not evalu-ate nelarabine, because it was expected that the costs would not reach the threshold for additional funding.

Table 3.3-2: Main remarks on different aspects from the reimbursement evaluations of nelarabine

HAS RIZIV SMC Date 19.12.2007 01.06.2008 07.03.2008 Effectiveness significant improvement

in actual benefit presented main efficacy results

meaningful response rates

Safety few safety data presented main AEs presented main AEs Cost-effectiveness – – highly dependent on HSCT Budget impact – max. € 510,134 per year less than £ 107,000 per year Severity of disease – – – Easeofuse – – – Recommended yes yes yes Conditions only to as a bridge to HSCT

Abbreviations: HAS – Haute Autorité de Santé, RIZIV – RijksInstituut voor Ziekte- en InvaliditeitsVerzekering, SMC – Scottish Medicines Consortium, AE – adverse event, HSCT – Hematopoietic stem cell transplant

3.4 Trabectedin – Yondelis

3.4.1 Indication

Soft tissue sarcoma (STS) is a cancer that begins in the muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body [76]. The World Health Organization has defined more than 50 histological subtypes [77]. The prevalence of STS in Europe is estimated at 23.7/100,000 [37]. STS is diag-nosed by means of a biopsy for microscopic examination to determine the histologic type and tumour grade. Morphologic diagnosis is often comple-mented by ancillary techniques like immunohistochemistry, classical cytoge-netics, electron microscopy and molecular genetic testing [78]. Prognostic fac-tors in STS are the patient’s age and the size, histologic grade, mitotic activity, and stage of the tumour [76].

Treatment

Factors of influence on STS treatment are the site of the tumour (e.g. head and neck, trunk, extremities) and stage of the tumour, for which multiple systems are used. The main treatment for localised disease is surgery. Surgi-cal margins in STS are classified as intralaesional, marginal, wide and radi-cal. Radiotherapy is applied in intermediate or high grade STS, large deep low grade sarcomas and incompletely resected tumours that are close to im-portant structures [77]. Radiation therapy can be administered as primary therapy, preoperatively or postoperatively [78]. Chemotherapy is used in high grade tumours to shrink the tumour before surgery. Postoperatively it can increase relapse-free-survival. For advanced, unresectable or metastatic dis-ease several regimens are available [78].

nelarabine was not evaluated by NICE

and CVZ

STS is a cancer that begins in the muscle, fat,

fibrous tissue, blood vessels, or other

supporting tissue of the body

prevalance is estimated

at 23.7/100,000

Treatment can consist of surgery, radiotherapy

and chemotherapy

Results

LBI-HTA | 2013 33


Trabectedin was initially obtained by isolation from the marine tunicate Ec-teiniascidia turbinate, nowadays it is produced synthetically. Trabectedin pre-dominantly binds to the minor groove of DNA and thereby delaying S-phase progression and inducing G2/M arrest. The precise mechanism of action how-ever, is not completely understood [79].


Trabectedin was authorised by the EMA on 17 September 2007, for the treat-ment of patients with advanced STS, after failure of anthracyclines and ifos-famide, or who are unsuited to receive these agents. Efficacy data are based mainly on liposarcoma and leiomyosarcoma patients. An application for Mar-keting Authorisation submitted in November 2001 had previously been re-jected [80].

Efficacy

In the first application, four phase I studies in patients with solid tumours were provided. In the second application an additional phase I study and a randomised, multi-centre, open-label study of trabectedin administered in two different schedules in patients with metastatic liposarcoma or leiomyo-sarcoma following treatment with an anthracycline and ifosfamide (ET743-STS-201) were submitted.

This pivotal study ET743-STS-201was originally designed to select the most appropriate dosing schedule for further testing. After preliminary descriptive data suggested that one of the two treatment schedules would be more effi-cacious, the study was extended and the protocol amended, to allow for a di-rect comparison between treatment schedules. Information on the inclusion criteria and the intervention is missing from the EPAR but can be found in the article by Demetri et al, 2009 [81]. After the protocol amendment, pa-tients were randomly assigned to one of two treatment schedules; trabecte-din 1,5mg/m2 in a 24-h infusion once every three weeks (q3wk 24-h) or tra-bectedin 0,58mg/m2 in a 3-h infusion weekly every three out of four weeks (qwk 3-h). Crossover to the alternative treatment schedule was allowed after progressive disease. After the protocol amendment, the primary endpoint was changed to time to progression (TTP), calculated as the time between date of randomisation and date of disease progression. Secondary endpoints were overall objective response, progression-free survival and overall survival. Eligibility criteria included ≥18 years of age, histological confirmation of liposarcoma or leiomyosarcoma, unresectable and/or metastatic disease and prior treatment with at least an anthracycline and ifosfamide (combined or sequential). Tumours were assessed every eight weeks by a blinded independ-ent review of diagnostic imaging by two radiologists, with a third radiologist resolving discrepancies [81].

At the time of the application to EMA, 266 patients had been randomly as-signed to a treatment arm and were included in the primary analysis. The two study groups were well balanced for both demographic characteristic as well as prognostic variables. Time to progression at the primary analysis was 2.1 months (95 %CI 1.9-3.6) for the qwk 3-h treatment arm and 3.8 months (95 % CI 2.1-5.4) for the q3wk 24-h treatment arm. Although not statistically

precise mechanism is not completely understood

on pivotal, double arm, uncontrolled, phase II study, 266 patients


34 LBI-HTA | 2013

significant, consistent trends were seen for PFS and OS. An updated report including new statistical analyses showed statistically significant results on the primary endpoint TTP. An additional survival analysis was requested by the CHMP. No statistically significant difference in survival was shown, but this might be due to crossover between treatment arms.

Table 3.4-1: Main outcomes of study ET743-STS-201

Primary analysis q3wk 24-h qwk 3-h n=132 n=134 TTP, median months [95 %CI] 3.8 [2.1-5.4] 2.1 [1.9-3.6] PFS, median months [95 %CI] 3.5 [2.0-4.5] 2.1 [1.9-3.4] OS, median months [95 %CI] 16.7 [12.2-n.r.] 11.8 [8.9-14.9] Ancillary analysis q3wk 24-h qwk 3-h n=136 n=134 TTP, median months [95 %CI] 3.7 [2.1-5.4] 2.3 [2.0-3.5]

TTP – Time to progression, PFS – Progression free survival, OS – overall survival

Safety

After the last update, the assessment of safety was based on data from clini-cal trials in 569 patients treated with the recommended regimen in several cancer types. Approximately 91 % of the patients experienced any type of adverse event and around 40 % experienced a grade 3 or 4 adverse event. Most common adverse reactions were nausea, fatigue, vomiting, anorexia, neutropenia and increases in AST/ALT. Fatal adverse reactions have occurred in 1,9 %. Cumulative toxicity has not been observed [80].

Risk/Benefit

The EPAR states that trabectedin should ideally have been compared in an adequately designed and analysed randomised trial to best care or investiga-tor’s choice. This was not possible due to the absence of a control arm in the pivotal study. The applicant claimed that a comparison to best supportive care is considered very difficult in this patient population. The population of STS patients was considered heterogeneous and individual subpopula-tions are considered too rare for adequately powered randomised controlled trials to be conducted against best supportive care to explore factors associ-ated with response to treatment within reasonable time. Conclusively, due to the rarity of the disease, the CHMP decided by consensus that the risk/benefit ratio of trabectedin was favourable and that the marketing authorisation could be granted under exceptional circumstances. Routine pharmacovigi-lance was considered adequate to monitor the safety of the product.


Because the authorisation was an approval under exceptional circumstances, the marketing authorisation holder had to conduct a further investigation in order to elucidate whether predictorsof response to trabectedin in patients with STS could beidentified. The final study report should have been sub-mitted by 30 June 2012 [82]. This report is still awaited [83].


STS subtypes too rare for a RCT

specific obligations related to predictors

of response

Results

LBI-HTA | 2013 35


A search after additional published material of single-agent use of trabecte-din in STS resulted in 25 articles of phase II clinical trials, retrospective case series analyses and case reports (Table 3.4-2). The retrospective case series analyses mostly included patients in compassionate use programmes.

Table 3.4-2: Publications of single-agent use of trabectedin in patients with soft tissue sarcoma

Source Journal Type of Study No. ofPts Subtype Paz-Ares et al, 2012 [84]

Invest New Drugs

Phase II, uncontrolled

41 advanced or metastatis STS

Gronchi et al, 2012 [85]

Ann Oncol Phase II, uncontrolled

29 myxoid liposarcoma, non-metastatic

Baruchel et al, 2012 [86]

Eur J Cancer Phase II, uncontrolled

50 relapsed pediatric sarcomas

Monk et al, 2012 [87]

Gynecol Oncol

Phase II, uncontrolled

20 uterine leiomyosarcoma

Scho¨ffski et al, 2012 [88]

Onkologie Phase II, uncontrolled

28 STS

Sanfilippo et al, 2011[89]

Gynecol Oncol

Retrospective case series analysis

66 metastatic uterine leiomyosarcoma

Corrado et al, 2011 [90]

Gynecol Oncol

Case report 1 advanced uterine leiomyosarcoma

Schmitt et al, 2010 [91]

Mar Drugs Retrospective case series analysis

25 STS excluded Ewing’s and osteosarcoma

Fayette et al, 2010 [92]

Anticancer Drugs

Retrospective case series analysis

92 STS

Demetri et al, 2009 [81]

J Clin Oncol Phase II, secondline 270 advanced or metastatic liposarcoma or leiomyosarcoma

Grosso et al, 2009 [93]

Ann Oncol Retrospective case series analysis

32 myxoid liposarcoma

Amant et al, 2009 [94]

Int J Gynecol Cancer

Case report 5 uterine leiomyosarcoma

Roylance et al, 2007 [95]

Clin Oncol (R Coll Radiol)

Observational study 21 pre-treated advanced sarcoma

Grosso et al, 2007 [96]

Lancet Oncol Retrospective case series analysis

51 myxoid liposarcoma

Tewari et al, 2006 [97]

Gynecol Oncol

Case report 1 metastatic uterine leiomyosarcoma

Garcia-Carbonero et al, 2005 [98]

J Clin Oncol Phase II, first line 36 advanced STS

Therasse et al, 2005 [99]

Eur J Cancer Phase II, non-randomised

49 advanced STS

Le Cesne et al, 2005 [100]

J Clin Oncol Phase II, non-randomised

104 advanced STS

Blay et al, 2004[101]

Eur J Cancer Phase II, non-randomised

28 advanced GIST

Garcia-Carbonero et al, 2004 [102]


36 advanced STS

Yovine et al, 2004 [103]


54 advanced STS

Laverdiere et al, 2003 [104]

Cancer Phase II, non-randomised

25 osteosarcoma

trabectedin has been tested in many STS subtypes


36 LBI-HTA | 2013

Source Journal Type of Study No. ofPts Subtype Demetri et al, 2002 [105]

Anticancer Drugs

Phase II, non-randomised

72 metastatic or advanced STS

Brain et al, 2002 [106]

Anticancer Drugs

Phase II, non-randomised

54 advanced pretreated STS

Delaloge et al, 2001 [107]

J Clin Oncol Retrospective 29 sarcoma


Trabectedin was evaluated by all five agencies. The SMC was the only agen-cy that did not recommend trabectedin (Table 3.4-3).

In the decision document from 13 November 2008, RIZIV presents a brief overview of the results from the pivotal study, contra-indications and ease of use, the incidence of STS in Belgium and an estimation of the budget impact. Because trabectedin has orphan status, an economic evaluation is not neces-sary.

The NICE Guidance for trabectedin in the treatment of STS was published on 1 February 2010. Trabectedin was recommended with a patient access scheme, in which it is agreed that the acquisition costs of trabectedin for treatment needed after the fifth cycle are met by the manufacturer.

The clinical evidence submitted by the manufacturer included the pivotal trial and three additional uncontrolledphase II trials. As there were no con-trolled studies, historical control data from studies in the European Organi-sation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group (EORTC STBSG) database were used to approximate best supportive care (BSC). The Committee concluded this to be appropriate for this disease area. They noted that the median overall survival and progression free sur-vival for patients on the licenced dosage of trabectedin, exceeded that for pa-tients receiving BSC, therefore they concluded that trabectedin was a clini-cally effective treatment.

In the guidance a lot of attention is given to the determination of the ICER, which is eventually estimated at £ 34,500 per QALY gained, with inclusion of the patient access scheme.

HAS published a report on trabectedin on 02 April 2008 and based their as-sessment on the pivotal study from the EPAR. Due to the lack of data from studies versus “supportive care” or a formalised comparison with a historic cohort, they concluded that trabectedin offers no improvement in actual benefit (level V). They do however recommend it for inclusion on the list of medicines approved foruse by hospitals and various public services.

After an application by the manufacturer for reimbursement, CVZ issued a report on 28 April 2008 which did not recommend trabectedin for outpatient use [108]. It concluded that trabectedin as a second line therapy in leiomyo- and myxoid liposarcoma appeared efficacious, but that the sometimes severe, acute and deadly adverse effects make it unsuitable for outpatient use. In October 2009 the Dutch Federation for University Medical Centres applied for inclusion in the Orphan Drug policy, which was followed by a positive recommendation by CVZ on 22 February 2010 [109]. In this assessment, be-sides the EPAR, four additional studies were included (Yovine et al, Garcia-

RIZIV recommends trabectedin

NICE published

extenisve guidance, trabectedin is

recommended with a patient access scheme

a cost of £ 34,500 per QALY is accepted

HAS recommends

trabectedin

CVZ recommends

trabectedin only for inpatient use

Results

LBI-HTA | 2013 37

Carbonero et al, 2004, Le Cesne et al, Roylance et al, Table 3.4-2). Due to the lack of randomised, controlled trials, they conclude that trabectedin appears to be efficacious and that it may be possible to increase the period of stable disease. An increase in overall survival has however not been proven. As re-quired by the Orphan Drug policy, additional cost-effectiveness research is now being performed [110].

The evaluation by SMC from 11 August 2008 emphasised the limited efficacy data. The lack of comparisons with best supportive care or other therapy made it difficult to evaluate the additional clinical benefit. The cost-effectiveness evaluation submitted by the manufacturer was deemed unreliable. Where the manufacturer estimated the ICER to be £ 29,954 per QALY, the SMC had great doubts about the quality of the economic analysis and estimates the ICER to be at least £ 40,000. As a result, trabectedin is not recommended [111].

Table 3.4-3: Main remarks on different aspects from the reimbursement evaluations of trabectedin

CVZ HAS NICE RIZIV SMC Date 22.02.2010 02.04.2008 01.02.2010 01.02.2009 11.01.2008 Effectiveness appears to

be effective activity is minor and difficult to evaluate

clinically effective

presented main efficacy results

difficult to evaluate additional clinical benefit over standard practice

Safety sometimes severe and fatal

mainly haematological and hepatic toxicity

most AEs reversible and non-cumulative

presented main AEs

presented main AEs and comments from EPAR

Cost-effectiveness

£ 34,500 per QALY

around £ 40,000 or higher

Budget impact € 5.3 million per year

€ 242.798 a` € 353.161 per year

£ 243,000 in year 1 rising to £ 289,000 by year 5

Ease of use IV infusion central venous catheter

Recommended Yes Yes Yes* Yes No

* With patient access scheme

Abbreviations: CVZ – College voor Zorgverzekeringen, HAS – Haute Autorité de Santé, NICE – National Institute for Health and Clinical Excellence, RIZIV – Rijks Instituut voor Ziekte- en InvaliditeitsVerzekering, SMC – Scottish Medicines Consortium, AE – adverse event, EPAR – European public assessment report, QALY – Quality adjusted life-year

SMC does not recommend trabectedin on the basis of cost-effectiveness


38 LBI-HTA | 2013

3.5 Ceplene – histamine dihydrochloride

3.5.1 Indication

Acute myeloid leukaemia (AML) is a cancer of blood or bone marrow cells from the myeloid lineage (See chapter clofarabine). In 2008 the AML-sub-types were reclassified under WHO supervision and now incorporate and in-terrelate morphology, cytogenetics, molecular genetics, and immunologic mark-ers [112]. The older French-American-British (FAB) criteria relied solely on morphologic features [113]. Like in ALL, the leukaemia cells displace the healthy blood cells, which may lead to infection, anaemia and blood coagula-tion disorders. The estimated prevalence of AML in Europe is 16/100,000 [37].

Prognostic factors in AML can be divided into patient characteristics, like age and general health condition, and leukaemia cell characteristics, like the karyotype of the cells and the molecular genetics. The monitoring of minimal residual disease is also in AML a tool to improve risk stratification [112].

Treatment

Treatment strategies in AML differ from ALL strategies. AML treatment simi-larly starts with remission induction and is followed by postremission ther-apy. CNS prophylactic therapy and maintenance treatment however, are usu-ally not indicated [112, 114]. The current standard for remission induction therapy is three days of an anthracycline (daunorubicin or idarubicin) or mi-toxantrone, followed by seven days of cytarabine. CR is achieved in 60 % to 80 % of younger adults. There are multiple possibilities in postremission ther-apy, and in certain subtypes of AML some strategies have proven to be supe-rior to others. High-dose cytarabine has improved outcome in patients with certain cytogenetic abnormalities. Autologous HSCT is an alternative for post-remission therapy in patients with favourable or intermediate risk cy-togenetics. Allogeneic HSCT is associated with the lowest risk of relapse. This is attributed to both the high-dose regimen of the conditioning treatment and the graft-versus-leukaemia effect. Treatment related mortality limits the bene-fits unfortunately; therefore the risks associated with the transplant itself, e.g. comorbidities, should be an important factor in clinical decision making [112].


Histamine dihydrochloride (HDC) is a synthetic immune modulator, indi-cated for maintenance therapy for adult patients with AML in first remis-sion concomitantly treated with interleukin-2 (IL-2). IL-2 is deployed to ac-tivate natural killer cells and T-lymphocytes that kill tumour cells. IL-2 has been administrated to patients to prevent relapse in several randomised and non-randomised trials, but the result were inconsistent and failed to demon-strate a reduced frequency of relapse. The addition of HDC to improve the function of cytotoxic lymphocytes was based on in vitro and in vivo studies in multiple human malignant target cells and a phase II pilot study suggested it to be safe and feasible [115].

AML is a cancer of blood or bone marrow cells from the myeloid

lineage

leukaemia cell characteristics are an important prognostic

factor

treatment consists of remission induction and post remission therapy.

CNS prophylactic

therapy and maintenance treatment are usually

not indicated

histamine dihydrochloride is

used together with interleukin-2

Results

LBI-HTA | 2013 39


The application for marketing authorisation for Ceplene was submitted on 06 October 2006. After an initial refusal and re-examination by the EMA it was approved on 07 October 2008 as maintenance therapy indicated for adult patients with acute myeloid leukaemia in first remission, concomitantly treated with IL-2 [116].

Efficacy

The pivotal trial, study MP-MA-0201, was a randomised, open label, multi-center phase III trial with the main goal to compare the effect of HDC/IL-2 therapy versus no treatment on leukaemia free survival (LFS) in patients with acute myeloid leukaemia in complete remission. Three hundred twenty patients were included in the study and randomisation was stratified based on first or subsequent remission. The study showed a statistically significant difference in LFS in the population in first remission. Kaplan-Meier estimates of 3-year LFS were 26 % in the control group and 40 % in the HDC/IL-2 group (p=0,02). No significant differences were observed in the population in subsequent remission or in overall survival, but it should be noted that the study was not sufficiently powered for the latter [115, 116].

Safety

A total of 1,188 patients were treated with HDC and 689 control patients were part of the clinical development program. The most common adverse effects were flushing, hypotension, headache and injection site reactions. No study medication related deaths were reported. Quality-of-life levels were similar in both treatment groups [116].

Risk/Benefit

After an oral explanation by the applicant to the CHMP, to address the out-standing issues, the CHMP decided that the risk-benefit balance for Ceplene was unfavourable. The main reason for this decision was the dependence on one pivotal study [116]. In document CPMP/EWP/2330/99 the EMA states that there is no formal requirement to include two or more pivotal studies, but in the exceptional event of a submission with only one pivotal study, this has to be particularly compelling with respect to internal and external valid-ity, clinical relevance, statistical significance, data quality and internal con-sistency [117]. In the case of Ceplene, the CHMP considered the requirements of statistically compelling results not to be fulfilled. There was also only one supportive clinical phase II study available in only 39 patients. Thirdly, the pharmacological rationale was deemed to be weak and the supporting non-clinical data were not considered to be sufficient [116].

After the initial recommendation, the applicant provided detailed grounds for re-examination including the opinion of expert European biostatiticians to support the pivotal trial and a review of the pharmacological rationale. For the re-examination of Ceplene, the CHMP consulted a scientific advisory group (SAG) in oncology to obtain advice on different matters relating to the clinical efficacy. There were different views on the robustness of the efficacy data and the support of the pharmacological rationale within the SAG. Some considered the single pivotal trial not to provide conclusive evidence due to marked heterogeneity between participating countries/centres, insufficient

pivotal, controlled, phase III trial

safety data based on 1,188 patients

initially the CHMP decided against authorisation

a re-examination was performed and a scientific advisory group was consulted


40 LBI-HTA | 2013

support of pharmacological rationale, non-clinical data provided, absence of proof of concept in eradication minimal residual disease and finally the negative outcome of the clinical trials with HDC/IL-2 in other indications. Others considered the biological rationale to be sound and found the uncer-tainty of the individual effects of the combination less important and con-sidered the combination showed efficacy for a clinically relevant endpoint in a condition where there is a high medical need. Combined with the manage-able toxicity, the benefits were considered important, even in the absence of extensive supportive data [116].

After reconsideration the CHMP concluded that the pivotal study could be considered as exceptionally compelling, particularly due to the high quality of the conduct of the study, the clinically and statistically significant results, and the internal validity. Also, the pharmacological rationale was accepted. HDC was approved by majority decision. Further clinical data were however requested [116].


The marketing authorisation holder has to complete two post-authorisation obligations.

b A clinical study to evaluate the biomarkers and pharmacologic end-points of Ceplene plus low dose interleukin-2 in approximately 100 adult patients stratified by age greater or less than 60 years with acute myeloid leukemia in first complete remission (CR), with well charac-terized morphologic, cytogenetic and molecular profiles, to be com-pleted in the second quarter of 2013.

b A clinical study to evaluate minimal residual disease for the assess-ment of the anti-leukaemic activity of Ceplene plus low dose inter-leukin-2 in approximately 150 adult patients stratified by age greater or less than 60 years with acute myeloid leukemia in first complete remission, to be completed in the second quarter of 2013 [118].


Since the marketing authorisation in October 2008, only one additional clinical study has been performed. According to the information from clini-caltrials.gov, the final data collection for the primary outcome measures should have been completed in August 2012. There are no additional publi-cations for HDC in AML.


To date, only HAS, CVZ and SMC have issued a recommendation on Ce-plene; HAS a positive one, CVZ and SMC a negative (Table 3.5-1).

The HAS report from 1 December 2010 briefly mentioned the methodologi-cal shortcomings of pivotal trial, but also recognised the absence of alterna-tive maintenance treatments for AML patients and therefore gave a positive advice for the use of HDC in AML patients under 60 years in first remission that are ineligible for an allograft.

HDC was approved by majority decision

specific obligations concerned two

additional trials

there are no additional

publication for HDC in AML

HAS recommends HDC inspite of shortcomings

of pivotal trial

Results

LBI-HTA | 2013 41

CVZ released the most extensive evaluation of HDC on 26 September 2011, about three years after the marketing authorisation. In the evaluation a lot of attention was given to the methodological shortcomings of study MP-MA-0201 and consequentially they concluded that the positive effects of HDC (five-month gain in leukaemia free survival, no significant difference in overall survival) were insufficiently supported. An important shortcoming was the absence of information on induction therapies and the great heterogeneity that could be expected in these induction therapies. Additionally the differ-ence in effect on LFS between different countries, showed that the standard of care in a specific country was of influence on the LFS. Together with the fact that the study was performed between 1998 and 2002, this meant that there is great uncertainty if the chemotherapy received by patients in the study, corresponded with current practice.

The SMC advice from 17 December 2010 is less extensive. Their main issues in the assessment of effectiveness were the lack of data on prior induction and consolidation regimens and on subsequent treatments following relapse, mak-ing the interpretation of the OS data problematic. Additionally, clinical ex-perts indicated that the standard of care in AML had improved since the pivotal study was performed, hence HDC’s potential place in therapy was unclear. The SMC also evaluated a cost-utility analysis submitted by the manufacturer and judged it to be insufficiently robust.

Table 3.5-1: Main remarks on different aspects from the reimbursement evaluations of histamine dihydrochloride

CVZ HAS SMC Date 26.09.2011 01.12.2010 17.12.2010 Effectiveness insufficient evidence methodological weaknesses considerable uncertainty Safety no fatal AEs thrombocytopenia most

serious AE no fatal AEs

Cost-effectiveness – – considerable uncertainty Budget impact – – up to £ 1,2m per year Severity of disease – serious, life-threatening – Ease of use self-administrable – – Recommended no yes no

Abbrevations: CVZ – College voor Zorgverzekeringen, HAS – Haute Autorité de Santé, SMC – Scottish Medicines Consortium, AE – adverse event

CVZ does not recommend HDC for the treatment of AML

SMC does not recommend HDC for AML

42 LBI-HTA | 2013

4 Discussion

This report aims to provide insight into the authorisation under exceptional circumstances of oncology drugs. Since the founding of the EMA in 1995, eleven oncologic drugs have been authorised under exceptional circumstances, seven of which received a regular marketing authorisation later on. The four drugs that are still licenced under exceptional circumstances were included in this report.

4.1 EMA’s considerations and additional requirements

Two of the main questions we wanted to answer were; what were the main considerations of the CHMP to licence the included drugs under exceptional circumstances and what were the additional requirements for the marketing authorisation holder?

Two of the drugs, nelarabine and clofarabine, received a marketing authori-sation under exceptional circumstances, clearly because of the very small size of the population. ALL and LBL are diseases which have gained better and better outcomes in the past decades and fortunately there are not that much patients in second relapse. Secondly, even in the absence of adequately con-trolled trials, nelarabine and clofarabine treatment achieved meaningful re-sponse rates and duration of response in a significant proportion of patients, said the CHMP. The really short life-expectancy in patients in second re-lapse and the possibility to reach long-term survival with both nelarabine and clofarabine followed by HSCT shows the actual benefit to patients. Of course there are many uncertainties regarding the safety profiles, but those should be tackled by the specific obligations required by the CHMP.

For clofarabine the initial requests by the CHMP concerned only the user’s information package and a voluntary adverse event reporting system. During the 3rd annually reassessment, additional obligations were added concerning population pharmacokinetics and dose adjustments in patients with moder-ate renal impairments. In the monitoring of adverse effects, extra attention was to be given to the monitoring of veno-occlusive disease after HSCT. For nelarabine the CHMP required data from an on-going phase III Children’s Oncology Group study and a post-marketing surveillance study, to better de-fine the safety profile. For both drugs there were no requirements concern-ing additional efficacy data, which reflects the opinion of the CHMP that they achieved meaningful responses.

A review of the literature revealed barely any new information on single-agent treatment for the licenced indications, but fortunately clofarabine and nelarabine are currently tested in multiple multi-agent regimens in several clinical trials.

Histamine dihydrochloride was authorised only after a re-examination and by majority decision, not by consensus. It was the only drug with a random-ised phase III trial, owing to the much larger target population; patients with AML in remission. Rarity of the disease is therefore not clearly stated

nelarabine and clofarabine have a very small target population

uncertainties regarding safety are addressed in

specific obligations

publications on single-agent treatment

are scarce

justification for authorisation under

exceptional circumstances is unclear

Discussion

LBI-HTA | 2013 43

as the ground for exceptional circumstances. In fact, the grounds for excep-tional circumstances are not clear at all. Statistically significant results were only demonstrated for the surrogate endpoint leukaemia-free-survival, but not for overall survival.

For histamine dihydrochloride two additional studies were requested. A clinical study to evaluate the biomarkers and pharmacologic endpoints of histamine dihydrochloride plus low dose interleukin-2 in approximately 100 adults, to be completed in the second quarter of 2013 and a clinical study to evaluate minimal residual disease for the assessment of the anti-leukaemic activity of histamine dihydrochloride plus low dose interleukin-2 in approxi-mately 150 adult patients, to be completed in the second quarter of 2013. This is in line with the uncertainties and disagreement regarding the effi-cacy. In favour of histamine dihydrochloride are the relatively mild side-effects. Information from clinicaltrials.gov and the EMA website is unfortu-nately suggesting that the progress in the compliance to the CHMP require-ments is rather slow.

Trabectedin, like clofarabine and nelarabine, received its marketing authori-sation under exceptional circumstances due to the rarity of the disease. The literature search however, implies that soft tissue sarcoma is not nearly as rare as ALL or LBL in second relapse. Subtypes of STS are indeed rare, and are considered too rare for adequately powered randomised controlled trials by the CHMP. What is contradictory to this statement is that trabectedin is licenced for all types of STS, although it was mainly tested in leiomyo- and liposarcoma. It is also not clear why it was not possible to perform a com-parison to best supportive care. With respect to the safety of trabectedin, much more information was already available, since a lot of patients had been treated in compassionate use programs.

For trabectedin the CHMP required the MAH to elucidate whether predic-torsof response to trabectedin in patients with soft tissue sarcoma could bei-dentified. The final study report was to be submitted by 30 June 2012, but is still awaited by the EMA. Outside of the trials of the manufacturer, trabect-edin has been tested in numerous clinical trials in the past few years and even extended its licence to a second indication. It is likely that more infor-mation will become available on the efficacy in different subtypes of STS.

Table 4.1-1: Compliance to additional requirements requested by the CHMP

Clofarabine Nelarabine Trabectedin Histamine dihydrochloride Year of authorisation 2006 2007 2007 2008

Requirements for additional data

Safety and pharmacokinetic data

Safety data Predictors of response

Biomarkers, pharmacologic endpoints and minimal residual disease

Delivered Yes Partly No No

no additional publications at all Specific obligations regarding two additional clinical trials

STS is less rare, but subtypes are lo¨ack of comparison to best supportive care is not explained

specific obligations regarding predictors of response


44 LBI-HTA | 2013

4.2 Reimbursement evaluations

When analysing the reimbursement decisions, it becomes clear that CVZ and NICE put a lot more effort into their assessments than RIZIV, HAS and SMC. In the assessments of RIZIV, when it comes to effectiveness and safety, no opinion is given on the quality of the evidence at all; they consist merely of a short summary of outcomes and adverse effects. The assessments of HAS are a little more extensive, but not very critical either. Both agen-cies have not rejected any of the assessed drugs.

SMC does not perform really extensive evaluations, but is more critical of the submitted evidence on effectiveness, safety and cost-effectiveness. As they apply a strict cost-effectiveness threshold, not all the drugs were recom-mended. Clofarabine and nelarabine were recommended for restricted use, but histamine dihydrochloride and trabectedin were both not recommended.

The single technology evaluations of NICE are an extensive, but also time consuming process. The evaluation of trabectedin is very thorough and there-fore provides an opportunity for trabectedin to be widely implemented into practice in England. The other three drugs have not been evaluated, but the publication by O’Connor et al, 2011 [44] shows that clofarabine is being used in England.

CVZ has evaluated three of the four drugs and recommended two of them. Their assessments are thorough and critical and separate the therapeutic and economic aspect. Drugs are not always recommended. As coverage with evidence development is always a condition for orphan or really expensive inpatient drugs, all drugs will be re-evaluated after about four years.

Table 4.2-1: Reimbursement decisions per agency

Reimbursement Clofarabine Nelarabine Trabectedin Histamine

dihydrochloride SMS Restricted Restricted No No HAS Yes Yes Yes Yes CVZ Yes NA Yes No RIZIV Restricted Yes Yes NA NICE NA NA Yes, with PAS NA

Abbreviations: CVZ – College voor Zorgverzekeringen, HAS – Haute Autorité de Santé, NICE – National Institute for Health and Clinical Excellence, RIZIV – Rijks Instituut voor Ziekte – en Invaliditeits Verzekering, SMC – Scottish Medicines Consortium, NA – Not applicable, PAS – Patient access scheme

NICE and CVZ produce extensive evaluations,

RIZIV and HAS are very brief

SMC is very concerned with cost-effeciveness

Discussion

LBI-HTA | 2013 45

4.3 Patient access and patient access schemes

There was only one patient access scheme identified. NICE recommended trabectedin after the manufacturer proposed a patient access scheme in which it is agreed that the acquisition costs of trabectedin for treatment needed af-ter the fifth cycle are met by the manufacturer.

Coverage with evidence development is always required in the Netherlands for inpatient pharmaceuticals applying for additional financing. Usually this is paid for by the manufacturer, but in the case of trabectedin, the research is financed by The Netherlands Organisation for Health Research and De-velopment. Since the request for additional financing of these drugs is done by the clinicians or hospital organisations and not by the manufacturer, it is not necessarily a patient access scheme.

In the end the most important question is if patients actually gained access to drugs through the market authorisation under exceptional circumstances. This can unfortunately not completely be extracted from just the reimburse-ment decisions. For the Netherlands and England a negative opinion does not strictly mean that a drug is not accessible, because hospitals can decide to pay for it. It is however unlikely. In the case that a drug is not assessed, access to it is rather unpredictable. In France, Belgium and Scotland how-ever, a drug certainly needs a positive recommendation to be accessible.

In France all four drugs received a positive recommendation and nelarabine, clofarabine and trabectedin are on the T2A list for additional funding. This makes it very probable that French patients have access to all four drugs.

In Belgium the three drugs that were assessed, nelarabine, clofarabine and trabectedin, received a positive recommendation and are reimbursed. They are likely to be accessible for all patients. Histamine hydrochloride was not evaluated and is therefore not reimbursed. Although it is not as expensive as the other three drugs, it is unlikely that it’s affordable to many of the patients.

NICE recommended trabectedin, which makes it mandatory to be available. Since England works with a negative list, the other three drugs are in theory reimbursable. Clofarabine has been used in practice, but it is not clear to which extent.

For Scotland it is more clear which drugs are available. Only nelarabine and clofarabine got a positive recommendation under specific conditions. Tra-bectedin and histamine dihydrochloride are very likely not accessible. Within the NHS system however, Scottish patients can travel to England to receive treatment. With the very strict cost-effectiveness criteria applied by the SMC, a lot of new medicines will likely not or with a delay be available in Scot-land.

In the Netherlands a positive recommendation is not a necessity for treat-ment in the hospitals. Histamine dihydrochloride is an outpatient pharma-ceutical and with the negative recommendation therefore not reimbursed. The conditional funding for trabectedin and clofarabine made the drugs ac-cessible in certain academic hospitals. With the Netherlands being so small, they should be accessible to all patients. Nelarabine was not evaluated be-cause it wouldn’t reach the cost threshold for additional funding. Hospitals have the option to pay it from their budget.

one patient access scheme identified for trabectedin

coverage with evidence development is very common in the Netherlands

patient access cannot completely be extracted from reimbursement decisions

HAS recommended all four drugs

RIZIV recommended the three drugs it assessed

NICE evaluated one drug and recommended it

SMC recommended just two drugs with restrictions

CVZ recommended two of the three drugs it evaluated


46 LBI-HTA | 2013

4.4 Conclusions and recommendations

With the authorisation of oncology drugs under exceptional circumstances the EMA has partially succeeded in providing safe and effective drugs to pa-tients with very rare cancers. For nelarabine and clofarabine the additional clinical data up to now were limited, but several clinical trials are planned and the benefit to patients has been shown. When evaluated by reimburse-ment agencies, these two drugs always received a positive recommendation, which makes them accessible to patients.

For trabectedin a lot of new information has become available and the indi-cation was even extended. The reason for the SMC to not recommend it, was the cost-effectiveness. For trabectedin it can be argued that the authorisation under exceptional circumstances wasn’t completely justified, since STS is not as rare. The STS subtypes however, are.

In the case of HDC the story is not that successful. The methodological weak-nesses in the pivotal trial made CVZ and SMC issue a negative recommen-dation and the by the CHMP requested trials have still not been performed. Time will tell if histamine dihydrochloride can become a successful treat-ment.

The criteria for authorisation under exceptional circumstances are not strictly defined, which gives the CHMP more freedom to apply this policy when they think it will be of benefit to the patient. This is acceptable, but a clearer statement of the justification is welcome. Additional requirements by the CHMP are often not met within the set time-frame.

It is clear that EMA and reimbursement agencies have a different perspec-tive when they evaluate a drug. As innovative orphan drugs are introduced on the market, it cannot always be expected that they immediately prove their cost-effectiveness, they might be of great benefit to the patients how-ever.

To retain the development of medicines for very rare diseases, it is important that industry, EMA and reimbursement agencies consult with each other. Scientific advice to the industry by EMA is highly recommended. Addition-ally the industry should pay more attention to the requirements of the ‘fourth hurdle’; for example include the collection of utility data in the trial design, which is necessary for cost-effectiveness assessments. In return a new anti-cancer drug could be given some time to prove itself in clinical practice. Conditional coverage with evidence development, as performed in the Neth-erlands, seems a good option. The involvement of the clinicians is an advan-tage, since small pharmaceutical companies may not always have the exper-tise and financial means to perform this evidence development by them-selves in a reasonable time-frame. It is then in the interest of the patient that the additional funding for this research is available. Since the patient popu-lations in these cases are small, international collaborations are highly rec-ommended. EU funding would then be a possibility.

clofarabine and nelarabine are currently

tested in multiple clinical trials and where

always recommended when evaluated

for trabectedin a lot of new information has

become available

HDC was only recommended in

France and there are no additional publications

the CHMP should be more clear about the

justification for authorisation under

exceptional circumstances

more collaboration between the industry,

EMA and reimbursement agencies is needed in the

development of drugs for very rare diseases

conditional coverage

with evidence development is a good

option

References

LBI-HTA | 2013 47

5 References

[1] Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on Orphan Medicinal Products, European Parliament and The Council, Editor. 2000, Official Journal of the European Communities.

[2] Committee for Medicinal Products for Human Use, Guideline on Procedures for the Granting of a Marketing Authorisation under Exceptional Circumstances, Pursuant to Article 14 (8) of Regulation NO 726/2004. 2005: London.

[3] Paul, J.E. and P. Trueman, ‘Fourth hurdle reviews’, NICE, and database applications. Pharmacoepidemiology and Drug Safety, 2001. 10(5): p. 429-438.

[4] McCabe, C., et al., Market and patient access to new oncology products in Europe: a current, multidisciplinary perspective. Annals of Oncology, 2009. 20(3): p. 403-412.

[5] Niraula, S., et al., The Price We Pay for Progress: A Meta-Analysis of Harms of Newly Approved Anticancer Drugs. J Clin Oncol, 2012.

[6] Apolone, G., et al., Ten years of marketing approvals of anticancer drugs in Europe: regulatory policy and guidance documents need to find a balance between different pressures. Br J Cancer, 2005. 93(5): p. 504-9.

[7] Kesselheim, A.S., J.A. Myers, and J. Avorn, Characteristics of clinical trials to support approval of orphan vs nonorphan drugs for cancer. Jama, 2011. 305(22): p. 2320-6.

[8] Joppi, R., V. Bertele, and S. Garattini, Orphan drug development is not taking off. Br J Clin Pharmacol, 2009. 67(5): p. 494-502.

[9] European Medicines Agency, Orphan medicines in numbers: the success of ten years of orphan legislation. 2010.

[10] Wild C, Hintringer K, and Nachtnebel A, Orphan Drugs in Oncology. Pharmaceutical Policy and Law 2011. 13: p. 1-11.

[11] Bignami, F., Eurordis survey on orphan drugs availability in Europe, in 6th Eurordis Round Table of Companies Workshop. 2007: Barcelona.

[12] European Commission. The ‘centralised procedure’ for authorising medicinal products is laid down in Regulation (EC) No 726/2004.. 2013 [cited 2013 21 January]; Available from: http://ec.europa.eu/health/authorisation-procedures-centralised_en.htm.

[13] Haffner, M.E., J. Whitley, and M. Moses, Two decades of orphan product development. Nat Rev Drug Discov, 2002. 1(10): p. 821-825.

[14] Davies, J.E., S. Neidle, and D.G. Taylor, Developing and paying for medicines for orphan indications in oncology: utilitarian regulation vs equitable care[quest]. Br J Cancer, 2012. 106(1): p. 14-17.

[15] Committee for Medicinal Products for Human Use, Guideline on the scientific application and the practical arrangements necessary to implement Commission Regulation (EC) No 507/2006 on the conditional marketing authorisation for medicinal products for human use falling within the scope of Regulation (EC) No 726/2004, European Medicines Agency, Editor. 2006: London.

[16] Kleijnen, S., W. Goetsch, and A. d´Andon, EUnetHTA JA WP5: Relative Effectiveness Assessment (REA) of Pharmaceuticals. Background Review. 2011.

[17] Saltman, R.B., R. Busse, and J. Figueras, eds. Social health insurance systems in western Europe. European Observatory on Health Systems and Policies Series, ed. Josep Figueras, et al. 2004, Open University Press, McGraw-Hill Education: Maidenhead.

[18] Sociale Zekerheid: Alles wat je altijd al wilde weten, FOD Sociale Zekerheid, Editor. 2012: Brussel.

[19] The NHS Structure. 2013 [cited 2013 22 January]; Available from: http://www.nhs.uk/NHSEngland/thenhs/about/Pages/nhsstructure.aspx.

http://ec.europa.eu/health/authorisation-procedures-centralised_en.htm

http://www.nhs.uk/NHSEngland/thenhs/about/Pages/nhsstructure.aspx


48 LBI-HTA | 2013

[20] National Institute of Health and Clinical Excellence. What we do. 2012 [cited 2013 22 January]; Available from: http://www.nice.org.uk/aboutnice/whatwedo/what_we_do.jsp.

[21] Guide to the single technology appraisal process. 2009, National Institute for Health and Clinical Excellence,: London.

[22] National Institute of Health and Clinical Excellence, Appraising treatments which may extend life, at the end of life. 2009.

[23] Österreichisches Bundesinstitut Für Gesundheitswesen, Surveying, Assessing and Analysing the Pharmaceutical Sector in the 25 EU Member States, European Communities, Editor. 2006.

[24] Van der Meijden, C. and C. Grahlmann, Procedure beoordeling extramurale geneesmiddelen. 2011, Ministerie van Volksgezondheid, Welzijn en Sport en College voor zorgverzekeringen.

[25] Kuijpers, M.R. and W.G.M. Toenders, Procedure beoordeling intramurale geneesmiddelen. 2006, College voor zorgverzekeringen: Diemen.

[26] Beleidsregel dure geneesmiddelen, Nederlandse Zorgautoriteit, Editor. 2011.

[27] Beleidsregel weesgeneesmiddelen, Nederlandse Zorgautoriteit, Editor. 2011.

[28] Health Rights Information Scotland, New medicines in Scotland– who decides what the NHS can provide?, NHS Scotland, Editor. 2010.

[29] Carlson, J.J., et al., Linking payment to health outcomes: A taxonomy and examination of performance-based reimbursement schemes between healthcare payers and manufacturers. Health Policy, 2010. 96(3): p. 179-190.

[30] Walker, S., et al., Coverage with evidence development, only in research, risk sharing, or patient access scheme? A framework for coverage decisions. Value Health, 2012. 15(3): p. 570-9.

[31] Green, C., et al., Bortezomib for the treatment of multiple myeloma patients. Health Technol Assess, 2009. 13 Suppl 1: p. 29-33.

[32] Binnendijk, D., Fabrikant betaalt niet-succesvolle behandeling, in CVZ Magazine. 2012, College voor Zorgverzekeringen,: Diemen.

[33] Sunitinib for the first-line treatment of advanced and/or metastatic renal cell carcinoma (TA169), in NICE technology appraisal guidance. 2009, National Institute for Health and Clinical Excellence: London.

[34] Gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer (TA192), in NICE technology appraisal guidance. 2010, National Institute for Health and Clinical Excellence: London.

[35] National Cancer Institute. Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®). 2012 [cited 12 November 2012]; Available from: http://www.cancer.gov/cancertopics/pdq/treatment/childALL/Patient.

[36] Coebergh, J.W.W., et al., Leukaemia incidence and survival in children and adolescents in Europe during 1978-1997. Report from the Automated Childhood Cancer Information System project. European Journal of Cancer, 2006. 42(13): p. 2019-2036.

[37] Prevalence of rare diseases: Bibliographic data, in Orphanet report series; Rare diseases collection. 2012, Orphanet.

[38] Pui, C.-H. and W.E. Evans, Treatment of Acute Lymphoblastic Leukemia. 2006. p. 166-178.

[39] Network, N.C.C. (2012) Acute Lymphoblastic Leukemia. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Volume,

[40] Einsiedel, H.G., et al., Long-term outcome in children with relapsed ALL by risk-stratified salvage therapy: results of trial acute lymphoblastic leukemia-relapse study of the Berlin-Frankfurt-Munster Group 87. J Clin Oncol, 2005. 23(31): p. 7942-50.

http://www.nice.org.uk/aboutnice/whatwedo/what_we_do.jsp

http://www.cancer.gov/cancertopics/pdq/treatment/childALL/Patient

References

LBI-HTA | 2013 49

[41] Committee for Medicinal Products for Human Use, Evoltra: EPAR – Scientific Discussion 2007, European Medicines Agency: London.

[42] Parker, W.B., et al., Effects of 2-chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)adenine on K562 cellular metabolism and the inhibition of human ribonucleotide reductase and DNA polymerases by its 5’-triphosphate. Cancer Res, 1991. 51(9): p. 2386-94.

[43] Committee for Medicinal Products for Human Use, Evoltra: EPAR – Procedural steps taken and scientific information after authorisation 2012, European Medicines Agency: London.

[44] O’Connor, D., et al., Early UK experience in the use of clofarabine in the treatment of relapsed and refractory paediatric acute lymphoblastic leukaemia. Br J Haematol, 2011. 154(4): p. 482-5.

[45] Barba, P., et al., Clofarabine-based chemotherapy for relapsed/refractory adult acute lymphoblastic leukemia and lymphoblastic lymphoma. The Spanish experience. American Journal of Hematology, 2012. 87(6): p. 631-634.

[46] Kearns, P., et al., BIOV-111 a European Phase II Trial of Clofarabine (Evoltra(R)) in Refractory and Relapsed Childhood Acute Lymphoblastic Leukemia. 2006. p. 1859-.

[47] Genzyme, Briefing Package for Oncologic Drugs Advisory Committee (ODAC) Meeting 08 February 2011. 2010.

[48] McGregor, B.A., et al., The use of higher dose clofarabine in adults with relapsed acute lymphoblastic leukemia. Am J Hematol, 2009. 84(4): p. 228-30.

[49] Johnston, D.L. and K.M. Mandel, Fatal skin and liver toxicity in a patient treated with clofarabine. Pediatric Blood & Cancer, 2008. 50(5): p. 1082-1082.

[50] Jeha, S., et al., Phase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. J Clin Oncol, 2006. 24(12): p. 1917-23.

[51] Choi, J. and F. Foss, Efficacy of low dose clofarabine in refractory precursor T- acute lymphoblastic leukemia. Yale J Biol Med, 2006. 79(3-4): p. 169-72.

[52] Jeha, S., et al., Clofarabine, a novel nucleoside analog, is active in pediatric patients with advanced leukemia. Blood, 2004. 103(3): p. 784-9.

[53] Kantarjian, H., et al., Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia. Blood, 2003. 102(7): p. 2379-86.

[54] Kantarjian, H.M., et al., Phase I clinical and pharmacology study of clofarabine in patients with solid and hematologic cancers. J Clin Oncol, 2003. 21(6): p. 1167-73.

[55] Commissie Tegemoetkoming Geneesmiddelen, Aanvraag tot vergoedbaarheid van de specialiteit EVOLTRA 1mg/ml concentraat voor oplossing voor infusie, Flacons 4 x 20 ml, Ministerie van Sociale Zaken, Editor. 2008.

[56] Transparency Committee, EVOLTRA 1 mg/ml, solution to be diluted for infusion. 2006, Haute Autorité de Santé.

[57] Hulp, C.F., Farmacotherapeutisch rapport clofarabine (Evoltra ®) bij de indicatie pediatrische acute lymfatische leukemie. 2007, College voor Zorgverzekeringen: Diemen.

[58] Scottish Medicines Consortium, clofarabine, 1mg/ml concentrate for solution for infusion (Evoltra®). 2006, NHS Scotland.

[59] Institute, N.C. Non-Hodgkin Lymphoma Home Page. 2013 [cited 2013 30 January]; Available from: http://www.cancer.gov/cancertopics/types/alphalist/l.

[60] Lambe, C.U., et al., 2-Amino-6-methoxypurine Arabinoside: An Agent for T-Cell Malignancies. 1995. p. 3352-3356.

[61] Committee for Medicinal Products for Human Use, Atriance: EPAR – Scientific Discussion. 2007, European Medicines Agency: London.

http://www.cancer.gov/cancertopics/types/alphalist/l


50 LBI-HTA | 2013

[62] Committee for Medicinal Products for Human Use, Atriance: EPAR – Product Information. 2012, European Medicines Agency: London.

[63] Gokbuget, N., et al., High single-drug activity of nelarabine in relapsed T-lymphoblastic leukemia/lymphoma offers curative option with subsequent stem cell transplantation. Blood, 2011. 118(13): p. 3504-11.

[64] Horibe, K., et al., [Phase I study of nelarabine in patients with relapsed or refractory T-ALL/T-LBL]. Rinsho Ketsueki, 2011. 52(6): p. 406-15.

[65] Papayannidis, C., et al., Complete paraplegia after nelarabine treatment in a T-cell acute lymphoblastic leukemia adult patient. Am J Hematol, 2010. 85(8): p. 608.

[66] Iino, M., [Severe liver injury following nelarabine chemotherapy for T-cell lymphoblastic lymphoma]. Rinsho Ketsueki, 2009. 50(1): p. 49-51.

[67] Sigalas, P., et al., Nelarabine induced complete remission in an adult with refractory T-lineage acute lymphoblastic leukemia: A case report and review of the literature. Leuk Res, 2009. 33(7): p. e61-3.

[68] Alvarado, Y., et al., Nelarabine activity in acute biphenotypic leukemia. Leuk Res, 2007. 31(11): p. 1600-3.

[69] DeAngelo, D.J., et al., Nelarabine induces complete remissions in adults with relapsed or refractory T-lineage acute lymphoblastic leukemia or lymphoblastic lymphoma: Cancer and Leukemia Group B study 19801. Blood, 2007. 109(12): p. 5136-42.

[70] Berg, S.L., et al., Phase II study of nelarabine (compound 506U78) in children and young adults with refractory T-cell malignancies: a report from the Children’s Oncology Group. J Clin Oncol, 2005. 23(15): p. 3376-82.

[71] Kurtzberg, J., et al., Phase I study of 506U78 administered on a consecutive 5-day schedule in children and adults with refractory hematologic malignancies. J Clin Oncol, 2005. 23(15): p. 3396-403.

[72] Commissie Tegemoetkoming Geneesmiddelen, Demande de remboursement de la spécialité pharmaceutique: ATRIANCE 5 mg/ml solution pour perfusion, flacons 6 x 5 mg/ml, Ministerie van Sociale Zaken, Editor. 2008.

[73] Transparency Committee, ATRIANCE 5 mg/ml, Solution for Infusion. 2007, Haute Autorité de Santé.

[74] Scottish Medicines Consortium, Nelarabine, 5mg/ml solution for infusion (Atriance®). 2008, NHS Scotland.

[75] National Institute of Health and Clinical Excellence. Topics considered for potential technology appraisal but not referred to NICE. 2009 [cited 2013 30 January]; Available from: http://www.nice.org.uk/getinvolved/topicselection/outcomes/notreferred.jsp.

[76] National Cancer Institute. Adult Soft Tissue Sarcoma Treatment (PDQ®). 2012 [cited 13 December 2012]; Available from: http://www.cancer.gov/cancertopics/types/soft-tissue-sarcoma.

[77] Sinha, S. and A.H. Peach, Diagnosis and management of soft tissue sarcoma. Bmj, 2010. 341: p. c7170.

[78] Network, N.C.C. (2012) Soft Tissue Sarcoma, NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Volume,

[79] Cioffi, A. and A. Italiano, Clinical and pharmacokinetic evaluation of trabectedin for the treatment of soft-tissue sarcoma. Expert Opinion on Drug Metabolism Toxicology, 2012. 8(1): p. 113-122.

[80] Committee for Medicinal Products for Human Use, Yondelis: EPAR – Scientific Discussion. 2007, European Medicines Agency: London.

[81] Demetri, G.D., et al., Efficacy and safety of trabectedin in patients with advanced or metastatic liposarcoma or leiomyosarcoma after failure of prior anthracyclines and ifosfamide: results of a randomized phase II study of two different schedules. J Clin Oncol, 2009. 27(25): p. 4188-96.

[82] Committee for Medicinal Products for Human Use, Yondelis: EPAR – Product Information. 2012, European Medicines Agency: London.

http://www.nice.org.uk/getinvolved/topicselection/outcomes/notreferred.jsp

http://www.cancer.gov/cancertopics/types/soft-tissue-sarcoma

References

LBI-HTA | 2013 51

[83] Committee for Medicinal Products for Human Use, Yondelis: EPAR – Procedural steps taken and scientific information after authorisation 2012, European Medicines Agency: London.

[84] Paz-Ares, L., et al., Trabectedin in pre-treated patients with advanced or metastatic soft tissue sarcoma: a phase II study evaluating co-treatment with dexamethasone. Invest New Drugs, 2012. 30(2): p. 729-40.

[85] Gronchi, A., et al., Phase II clinical trial of neoadjuvant trabectedin in patients with advanced localized myxoid liposarcoma. Ann Oncol, 2012. 23(3): p. 771-776.

[86] Baruchel, S., et al., A phase 2 trial of trabectedin in children with recurrent rhabdomyosarcoma, Ewing sarcoma and non-rhabdomyosarcoma soft tissue sarcomas: A report from the Children’s Oncology Group. European Journal of Cancer, 2012. 48(4): p. 579-585.

[87] Monk, B.J., et al., A phase II evaluation of trabectedin in the treatment of advanced, persistent, or recurrent uterine leiomyosarcoma: A gynecologic oncology group study. Gynecologic Oncology, 2012. 124(1): p. 48-52.

[88] Schöffski, P., et al., Administration of 24-h Intravenous Infusions of Trabectedin in Ambulatory Patients with Mesenchymal Tumors via Disposable Elastomeric Pumps: An Effective and Patient-Friendly Palliative Treatment Option. Onkologie, 2012. 35(1-2): p. 14-17.

[89] Sanfilippo, R., et al., Trabectedin in advanced uterine leiomyosarcomas: A retrospective case series analysis from two reference centers. Gynecologic Oncology, 2011. 123(3): p. 553-556.

[90] Corrado, G., et al., Prolonged clinical response to trabectedin in a heavily pretreated patient with advanced uterine leiomyosarcoma: A case report and literature review. Gynecologic Oncology, 2011. 121(2): p. 416-417.

[91] Schmitt, T., et al., Trabectedin for metastatic soft tissue sarcoma: a retrospective single center analysis. Mar Drugs, 2010. 8(10): p. 2647-58.

[92] Fayette, J., et al., Efficacy of trabectedin for advanced sarcomas in clinical trials versus compassionate use programs: analysis of 92 patients treated in a single institution. Anticancer Drugs, 2010. 21(1): p. 113-9.

[93] Grosso, F., et al., Trabectedin in myxoid liposarcomas (MLS): a long-term analysis of a single-institution series. 2009. p. 1439-1444.

[94] Amant, F., et al., Clinical outcome of ET-743 (Trabectedin; Yondelis) in high-grade uterine sarcomas: report on five patients and a review of the literature. Int J Gynecol Cancer, 2009. 19(2): p. 245-8.

[95] Roylance, R., et al., Experience of the Use of Trabectedin (ET-743, Yondelisâ“¢) in 21 Patients with Pre-treated Advanced Sarcoma from a Single Centre. Clinical Oncology, 2007. 19(8): p. 572-576.

[96] Grosso, F., et al., Efficacy of trabectedin (ecteinascidin-743) in advanced pretreated myxoid liposarcomas: a retrospective study. The Lancet Oncology, 2007. 8(7): p. 595-602.

[97] Tewari, D., et al., Activity of trabectedin (ET-743, Yondelis) in metastatic uterine leiomyosarcoma. Gynecologic Oncology, 2006. 102(3): p. 421-424.

[98] Garcia-Carbonero, R., et al., Ecteinascidin-743 (ET-743) for Chemotherapy-Naive Patients With Advanced Soft Tissue Sarcomas: Multicenter Phase II and Pharmacokinetic Study. 2005. p. 5484-5492.

[99] Therasse, P., et al., RECIST vs. WHO: Prospective comparison of response criteria in an EORTC phase II clinical trial investigating ET-743 in advanced soft tissue sarcoma. European Journal of Cancer, 2005. 41(10): p. 1426-1430.

[100] Le Cesne, A., et al., Phase II Study of ET-743 in Advanced Soft Tissue Sarcomas: A European Organisation for the Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group Trial. 2005. p. 576-584.

[101] Blay, J.Y., et al., A phase II study of ET-743/trabectedin (`Yondelis’) for patients with advanced gastrointestinal stromal tumours. European Journal of Cancer, 2004. 40(9): p. 1327-1331.

[102] Garcia-Carbonero, R., et al., Phase II and Pharmacokinetic Study of Ecteinascidin 743 in Patients With Progressive Sarcomas of Soft Tissues Refractory to Chemotherapy. 2004. p. 1480-1490.


52 LBI-HTA | 2013

[103] Yovine, A., et al., Phase II Study of Ecteinascidin-743 in Advanced Pretreated Soft Tissue Sarcoma Patients. 2004. p. 890-899.

[104] Laverdiere, C., et al., Phase II study of ecteinascidin 743 in heavily pretreated patients with recurrent osteosarcoma. Cancer, 2003. 98(4): p. 832-840.

[105] Demetri, G.D., ET-743: The US experience in sarcomas of soft tissues. Anti-Cancer Drugs, 2002. 13 Supplement(1): p. S7-S9.

[106] Brain, E.G., Safety and efficacy of ET-743: the French experience. Anticancer Drugs, 2002. 13 Suppl 1: p. S11-4.

[107] Delaloge, S., et al., Ecteinascidin-743: A Marine-Derived Compound in Advanced, Pretreated Sarcoma Patients’ Preliminary Evidence of Activity. 2001. 19(5): p. 1248-1255.

[108] Toenders, W.G.M., CFH-rapport 08/10 trabectedine (Yondelis®). 2008, College voor Zorgverzekeringen: Diemen.

[109] Commissie Farmaceutische Hulp, Farmacotherapeutisch rapport trabectedine (Yondelis®) bij de indicatie wekedelen sarcoom. 2010, College voor Zorgverzekeringen.

[110] ZonMW. Trabectedin for the treatment of patients with advanced soft tissue sarcoma (STS), after failure of anthracyclines and ifosfamide or patients unsuited to receive these drugs, in clinical practice. 2012 [cited 2012 17 January]; Available from: http://www.zonmw.nl/nl/projecten/project-detail/trabectedin-for-the-treatment-of-patients-with-advanced-soft-tissue-sarcoma-sts-after-failure-of/samenvatting/.

[111] Scottish Medicines Consortium, trabectedin 0.25 mg, 1 mg powder for concentrate for solution for infusion (Yondelis®). 2008, NHS Scotland.

[112] Döhner, H., et al., Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood, 2010. 115(3): p. 453-474.

[113] Cheson, B.D., et al., Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. J Clin Oncol, 1990. 8(5): p. 813-9.

[114] National Cancer Institute. Adult Acute Myeloid Leukemia Treatment (PDQ®) Treatment Option Overview. 2012 [cited 2013 30 January]; Available from: http://www.cancer.gov/cancertopics/pdq/treatment/adultAML/healthprofessional/page4.

[115] Brune, M., et al., Improved leukemia-free survival after postconsolidation immunotherapy with histamine dihydrochloride and interleukin-2 in acute myeloid leukemia: results of a randomized phase 3 trial. Blood, 2006. 108(1): p. 88-96.

[116] Committee for Medicinal Products for Human Use, Ceplene: EPAR – Public assessment report 2008, European Medicines Agency: London.

[117] Committee for proprietary medicinal products, Points to consider on applications with 1. meta-analyses; 2. one pivotal study. 2001, European Medicines Agency: London.

[118] Committee for Medicinal Products for Human Use, Ceplene: EPAR – Product Information. 2012, European Medicines Agency: London.

http://www.zonmw.nl/nl/projecten/project-detail/trabectedin-for-the-treatment-of-patients-with-advanced-soft-tissue-sarcoma-sts-after-failure-of/samenvatting/

http://www.cancer.gov/cancertopics/pdq/treatment/adultAML/healthprofessional/page4

http://www.zonmw.nl/nl/projecten/project-detail/trabectedin-for-the-treatment-of-patients-with-advanced-soft-tissue-sarcoma-sts-after-failure-of/samenvatting/

Documents

Marketing Authorisations under Exceptional Circumstances ...eprints.hta.lbg.ac.at/992/1/HTA-Projektbericht_Nr.65.pdf · Marketing Authorisations under Exceptional Circumstances for